5-phenoxyalkoxypsoralens and methods for selective inhibition of the voltage gated Kv1.3 potassium channel

ABSTRACT

Compositions of matter comprising 5-phenoxyalkoxypsoralen compounds and their method of synthesis and use. The compounds are useable to treat diseases or disorders in human or animal subjects, including autoimmune diseases. The compounds inhibit potassium channels, including the Kv1.3 channel and at least some of the therapeutic effects of such compounds may be due at least in part to potassium channel inhibition. In some embodiments, the compounds are more selective for certain potassium channels (e.g., Kv1.3 channels) than other potassium channels (e.g., Kv1.5 channels).

FIELD OF THE INVENTION

The present invention provides a) novel compositions of mattercomprising or consisting of 5-phenoxyalkoxypsoralens, b) methods fortreating and/or preventing diseases or disorders in human or animalsubjects, c) methods and kits for in vivo and/or in vitro inhibition ofthe selected types of potassium channels and d) the use of5-phenoxyalkoxypsoralen compositions in the manufacture ofpharmaceutical preparations for the treatment and/or prevention ofdiseases or disorders in human or animal subjects.

BACKGROUND OF THE INVENTION

T Cells and their Functions:

T cells are lymphocytes that have receptors capable of recognizingprotein fragments (antigens) derived from foreign, potentially harmfulproteins or organisms such as bacteria and viruses or from proteinspresent in the body of the host. Each T cell receptor recognizes adifferent string of amino acids, which comprise the antigen. Essentiallythere will always be at least one T cell receptor in the totalrepertoire of T cells, which will recognize any given antigen, which isin the body.

There are two main types of T cells, namely CD4+ helper T cells and CD8+killer T cells. Helper T Cells (Th) carry receptors that engage antigenspresent on the surfaces of an antigen-presenting cell (APC) such asdendritic cells and sometimes macrophages. It is only by engagement withan antigen present on an APC and a subsequent process known asco-stimulation that a Th cell can become activated so that it may attackthat specific antigen. Before the Th cell has become activated it isknown as a “naïve” T cell. After the Th cell has become activated itbecomes an “effector” T cell and wages an immune attack against theparticular antigen. After cells containing the antigen have beendestroyed, most of the effector T cells die. However, some effector Tcells remain in a resting or quiescent state and are then known as“memory T cells.” At least two types of Memory T cells exist, eachhaving different migratory characteristics and effector functions. Thefirst type of memory T cells are known as “effector memory T cells”(T_(EM)) and produce IFN-γ, TNF-α and IL-2 or pre-stored perforin (inthe case of CD8s) when they encouner an antigen. The second type ofmemory T cells, known as “central memory T cells” (T_(CM)), express thechemokine receptor CCR7 similar to naïve T cells and lack immediateeffector function. When T_(EM) cells encounter the same antigen thatinitially caused their activation, they quickly convert back to effectorT cells without the need for co-stimulation. Such rapid redeployment ofeffector T cells without the need for co-stimulation allows the immunesystem to attack the antigen in a very efficient manner.

Ion Channels: Molecular Targets for Pharmacologic Intervention

Ion channels are proteins embedded within the cell membrane that controlthe selective flux of ions across the membrane, thereby allowing therapid movement of ions during electrical signaling processes. Becauseion concentrations are directly involved in the electrical activity ofexcitable cells (e.g., neurons), the functioning (or malfunctioning) ofion channels can substantially control the electrical properties andbehavior of such cells. Indeed, a variety of disorders, broadly termedas “channelopathies,” are believed to be linked to ion channelinsufficiencies or dysfunctions.

Ion channels are referred to as “gated” if they can be opened or closed.The basic types of gated ion channels include a) ligand-gated channels,b) mechanically gated channels and c) voltage-gated channels. Inparticular, voltage-gated channels are found in neurons and musclecells. They open or close in response to changes in the potentialdifferences across the plasma membrane.

In recent years, drug development efforts have included work aimed atidentifying and characterizing various ion channels and designing agentsthat increase or decrease the flux of ions through those ion channels tobring about desired therapeutic effects.

Kv1.3 Channels and their Roll in T Cell Physiology.

The predominant voltage-gated potassium ion channel in humanT-lymphocytes is encoded by Kv1.3, a Shaker-related gene. Kv1.3 channelshave been characterized extensively at the molecular and physiologicallevel and are known to play a vital role in controlling T-lymphocyteproliferation, mainly by maintaining the membrane potential of restingT-lymphocytes. For example, encephalitogenic and arthritogenic rat Tcells that have been chronically activated with myelin antigens havebeen shown to express a unique channel phenotype (high Kv1.3 channelsand low IKCa1 channels), distinct from that seen in quiescent andacutely activated T cells (Beeton et al., 2001, Selective blockade of Tlymphocyte K(+) channels ameliorates experimental autoimmuneencephalomyelitis, a model for multiple sclerosis. Proc. Natl. Acad.Sci. USA 98:13942) and such findings have been confirmed in myelinantigen specific T cells from human patients suffering from multiplesclerosis (MS). Contrary to myelin-reactive T cells from healthycontrols and to mitogen or control antigen activated T cells from MSpatients, myelin reactive T cells from MS patients predominantlyexpressed surface markers of terminally differentiated effector memory Tcells (CCR7⁻CD45RA⁻) and exhibited the Kv1.3^(high)IKCa1^(low) phenotype(Wulff et al., The voltage-gated Kv1.3 K(+) channel in effector memory Tcells as new target for MS. 2003, J. Clin. Invest. 111:1703). In thesame study, it was shown that this special K⁺ channel phenotype made theproliferation of effector memory T cells highly sensitive to inhibitionby Kv1.3 blockers. Naïve and central memory T cells were only affectedat 10-fold higher concentrations of Kv1.3 blockers and could escapeKv1.3 inhibition during subsequent stimulation through the up-regulationof the calcium-activated potassium channel IKCa1. Thus, it may bepossible to develop a selective potassium channel blocker that willtarget the disease-inducing effector memory T cell population withoutaffecting the normal immune response.

Kv1.3 and IKCa1 Expression and Functional Roles in Naïve and MemoryT-Cells

Naïve, central memory (T_(CM)) and effector memory T (T_(EM)) cells areclassified based on the expression of the chemokine receptor CCR7 andthe phosphatase CD45RA. Naïve (CCR7⁺CD45RA⁺) and T_(CM) (CCR7⁺CD45RA⁻)cells migrate to the lymph node using CCR7 as an entry code, beforemigrating to sites of inflammation. In contrast, T_(EM) cells have theability to home directly to sites of inflammation, where they cansecrete high amounts of interferon (IFN-γ) and tumor necrosis factor-α(TNF-α) and exhibit immediate effector function. The expression patternsof Kv1.3 and IKCa1 change dramatically as naive cells become memorycells. At rest, CD4⁺ and CD8⁺ T-cells of all three subsets exhibit ˜200to 400 Kv1.3 channels, and 0 to 30 IKCa1 channels (Wulff et al., Thevoltage-gated Kv1.3 K(+) channel in effector memory T cells as newtarget for MS. 2003, J. Clin. Invest. 111:1703). Activation hasdiametrically opposite effects on channel expression; as naive andT_(CM) cells move from resting to proliferating blast cells, theytranscriptionally up-regulate IKCa1 to ˜500 channels per cell. Incontrast, activation of T_(EM) cells enhances Kv1.3 expression withoutany change in IKCa1 levels (Wulff et al., 2003, J. Clin. Invest.111:1703). Functional Kv1.3 expression increases dramatically within 15h of activation to a level of 1500 Kv1.3 channels/cell, remains elevatedfor the following 48 to 72 h, and then returns to baseline over the nextfive days (Beeton et al., A novel fluorescent toxin to detect andinvestigate Kv1.3 channel up-regulation in chronically activated Tlymphocytes. 2003, J. Biol. Chem. 278:9928)

The subset-specific channel expression has important functionalconsequences, since Kv1.3 and IKCa1 regulate Ca²⁺ entry into T-cellsthrough Ca²⁺-release-activated Ca²⁺ channels that exhibit ‘upside-down’voltage-dependence compared with voltage-gated Ca²⁺ channels. A negativemembrane potential drives Ca²⁺ entry through these channels. Theelectrochemical gradient supporting Ca²⁺ entry is initially large,resulting in significant Ca²⁺ influx. However, Ca²⁺ entry results indepolarization of the plasma membrane, limiting further influx. Tomaintain Ca²⁺ entry over the time scale required for gene transcription,a balancing cation efflux is necessary; this is provided by the effluxof K⁺ ions through Kv1.3 and/or IKCa1 channels, which supply theelectrochemical driving force for Ca²⁺ entry via membranehyperpolarization.

Depolarization resulting from Kv1.3 and IKCa1 blockade is inhibitory forCa²⁺ influx, signaling and lymphocyte activation. As Kv1.3 channelspredominate in resting T-cells of the three subsets, the Kv1.3 blockerShK, but not the IKCa1 blocker TRAM-34, suppress antigen ormitogen-driven activation. However, ShK is 10-fold more effective onT_(EM) cells than on naive and T_(CM) cells (IC₅₀ values of 400 pM and 4nM, respectively), due to the fact that the latter cells rapidlyup-regulate lkCa1 after stimulation and become less sensitive to Kv1.3inhibitors (Wulff et al., The voltage-gated Kv1.3 K(+) channel ineffector memory T cells as new target for MS. 2003, J. Clin. Invest.111:1703). Once IKCa1 is up-regulated in naïve and T_(CM) cells, thereactivation of these cells is sensitive to IKCa1 but not Kv1.3blockade. Naïve and T_(CM) cells can up-regulate IKCa1 following mitogenor antigen stimulation, even if their initial activation is suppressedby Kv1.3 blockade; and can consequently escape further inhibition byKv1.3 inhibitors (Wulff et al., 2003, J. Clin. Invest. 111:1703). Earlyin vivo studies support these in vitro findings. The Kv1.3 blockers MgTX(Koo et al., Blockade of the voltage-gated potassium channel Kv1.3inhibits immune responses in vivo. 1997, J. Immunol. 158:1520) andcorreolide (Koo et al., Correolide and derivatives are novelimmunosuppressants blocking the lymphocyte Kv1.3 potassium channels.1999, Cell Immunol. 197:99) effectively suppress the primarydelayed-type hypersensitivity (DTH) response in mini-pigs, but are muchless effective in suppressing the secondary DTH response, presumably dueto the fact that the activated naïve or T_(CM) cells involved haveup-regulated IKCa1 expression. In contrast, T_(EM) cells exclusivelyup-regulate Kv1.3 channels, and are persistently suppressed by Kv1.3inhibitors.

Kv1.3 and IKCa1 Expression and Functional Roles in Naïve and MemoryB-Cells

A similar change in potassium channel expression takes place during thedifferentiation from naïve into class-switched memory B cells. Whilenaïve (IgD⁺CD27⁻) and “early” memory B cells (IgD⁺CD27⁺) rely on IKCa1for their proliferation, class-switched (IgD⁻CD27⁺) memory B cells relyon Kv1.3 and their proliferation is therefore potently inhibited by theKv1.3 blockers ShK and Psora-4 (Wulff et al. K+ channel expressionduring B cell differentiation: implications for immunomodulation andautoimmunity. 2004. J. Immunol. 173:776-86). Thus, Kv1.3 blockersselectively target “late” memory responses in both the T- and B-celllineage should be useful for the treatment of autoimmune disorders.

Kv1.5 Channels and Regulation/Deregulation of Cardiac Rhythm

Ion flux through voltage gated potassium channels also plays a role inregulation of cardiac rhythms. Atrial fibrillation (AF) is a commoncardiac rhythm disturbance. AF can be treated or prevented by agentsthat prolong the atrial action potential duration and refractoriness.Indeed, drugs such as dofetilide, almokalant, amiodarone and d-sotalolcan effectively suppress AF. However, such drugs may also prolong theventricular action potential duration, thereby giving rise to lifethreatening or lethal ventricular arrhythmias. This potential forantiarrhythmic drugs to actually cause certain types of arrhythmiaswhile preventing others is sometimes referred to as the drug's“proarrhythmic potential.” Proarrhythmic potential is an importantdose-limiting factor in the use of antiarrhythmic drugs. In fact, acommon proarrhythmic event reported to result from the use oftraditional antiarrhythmic drugs that prolong ventricular repolarization(QT interval) to treat AF is a condition known as torsades de pointes,which is a rapid polymorphic ventricular tachycardia.

Because voltage gated Kv1.5 potassium channels are predominantly locatedin atrial tissue, drugs that inhibit Kv1.5 channels are being developedfor the treatment of AF (Brendel, J. and Peukert, S.; Blockers of theKv1.5 Channel for the Treatment of Atrial Arrhythmias; Current MedicinalChemistry—Cardiovascular & Hematological Agents, Volume 1, No. 3,273-287 (2003)). Drugs that selectively inhibit Kv1.5 channels couldprove to be a viable new approach for the treatment of AF with minimalor no proarrhythmic potential. However, it is also possible that,untoward inhibition of Kv1.5 channels in patients who have normal heartrhythms could induce an electrical imbalance and actually causearrhythmias in such patients. Thus, when developing drugs that areintended to inhibit potassium channels other than Kv1.5 (e.g., drugsintended to inhibit Kv1.3 channels to treat T cell mediated diseases),it may be desirable to design these drugs to display selectivity for thetarget potassium channels (e.g., Kv1.3 channels) over theheart-affecting Kv1.5 channels.

In view of the foregoing, there remains a need for the synthesis anddevelopment of new potassium channel inhibitors that are specific forcertain potassium channels over other potassium channels, therebyproviding specific therapeutic effects with minimal side effects.

SUMMARY OF THE INVENTION

The present invention provides 5-Phenoxyalkoxypsoralens, a new class ofsmall-molecules that block the Kv1.3 channel in the low nanomolar rangeand preferentially suppress the proliferation of effector memory T cellsand affect naïve and central memory T cells only at much higherconcentrations. Given the known in vitro and in vivo effects of peptideand non-peptide inhibitors of the Kv1.3 channel, the present inventionfurther comprises the therapeutic and/or diagnostic use of these5-phenoxyalkoxypsoralens for any diagnosis or treatment that resultsfrom or is facilitated by blocking or inhibiting of the Kv1.3 channel,including but not limited to the use of 5-phenoxyalkoxypsoralens asimmunosuppressants and/or for the treatment of multiple sclerosis,rheumatoid arthritis, graft rejection and/or any autoimmune disorders.

In accordance with the invention there are provided compositions ofmatter comprising or consisting of 5-phenoxyalkoxypsoralens of generalFormula I, as follows:

-   -   wherein:    -   n is 1 through 10, cyclic or acyclic and optionally substituted        or unsubstituted;    -   X is O, S, N, C Si or P; and    -   R1 is aryl, heterocyclyl or cycloalkyl and is optionally        substituted with one or more substituents selected from alkyl,        alkoxy, amino and its alkyl derivatives, acylamino, carboxyl and        its alkyl ester, cyano, halo, hydroxy, nitro and sulfonamido        groups.

Further in accordance with the present invention, there are providedpharmaceutical preparations for administration to human or veterinarypatients, said preparations comprising a 5-Phenoxyalkoxypsoralen ofGeneral Formula I above or a pharmaceutically acceptable salt thereofalone or in combination with pharmaceutically acceptable carriers,excipients and other ingredients commonly used in pharmaceuticalpreparations for oral, rectal, intravenous, intraarterial, intradermal,subcutaneous, intramuscular, intrathecal, sublingual, bucal, intranasal,trans-mucosal, trans-dermal, topical, other enteral, other parenteraland/or other possible route(s) of administration.

Still further in accordance with the invention, there are providedmethods for treating or preventing diseases or disorders in human oranimal subjects by administering to the subject a therapeutic orpreventative amount of a composition of General Formula I above or apharmaceutically acceptable salt or derivative thereof. Various diseasesand disorders may be treated or prevented by inhibiting selected typesof potassium channels. For example, compositions of the presentinvention that inhibit Kv1.3 channels on human T cells may be used totreat or prevent T cell mediated diseases or disorders, such as variousautoimmune diseases and disorders. The following are some non-limitingexamples of some T cell mediated autoimmune diseases or disorders thatmay be prevented or treated by the methods of the present invention,categorized with respect to the target organ that is principallyaffected by each such disease:

Nervous System: Gastrointestinal Tract: Multiple sclerosis Crohn'sDisease Myasthenia gravis Ulcerative colitis Autoimmune neuropathiesPrimary biliary cirrhosis such as Guillain-Barré Autoimmune hepatitisAutoimmune uveitis Endocrine: Ophthalmologic: Type 1 diabetes mellitusUveitis Addison's Disease Blood: Grave's Disease Autoimmune hemolyticanemia Hashimoto's thyroiditis Pernicious anemia Autoimmune oophoritisand Autoimmune orchitis thrombocytopenia Autoimmune ThyroiditisVascular: Multiple Organs and/or Temporal arteritis MusculoskeletalSystem: Anti-phospholipid syndrome Rheumatoid arthritis Vasculitidessuch as Systemic lupus erythematosus Wegener's granulomatosisScleroderma Behcet's disease Polymyositis Skin: DermatomyositisPsoriasis Spondyloarthropathies such as Dermatitis herpetiformisankylosing spondylitis Pemphigus vulgaris Sjogren's Syndrome VitiligoPemphigus Vulgaris Mycosis Fungoides Allergic Contact Dermatitis, AtopicDermatitis Lichen Planus PLEVA (Pityriasis lichenoides et varioliformsacuta),Irrespective of the particular organ(s) affected, T-lymphocytes arebelieved to contribute to the development of autoimmune diseases. Thecurrently available therapies for these diseases are largelyunsatisfactory and typically involve the use of glucocorticoids (e.g.methylprednisolone, prednisone), non-steroidal anti-inflammatory agents,gold salts, methotrexate, antimalarials, and other immunosuppressantssuch as cyclosporin and FK-506. Also, another T cell mediated disorderthat may be prevented or treated by the methods of the present inventionis graft vs. host disease and/or rejection of transplanted organs.T-lymphocytes play a central role in the immune response and they areresponsible, in large measure, for the rejection of many transplantedorgans. They are also responsible for the so-called graft-versus hostdisease in which transplanted bone marrow cells recognize and destroyMHC-mismatched host tissues. Accordingly, drugs such as cyclosporin andFK506 that suppress T-cell immunity are used to prevent transplantrejection and graft-versus-host disease. However, immunosuppressivetherapy with cyclosporin A is limited by severe side effects such asliver and renal damage. Selective inhibitors of the Kv1.3 potassiumchannel, such as the 5-Phenoxyalkoxypsoralens of General Formula Iabove, may be less likely to cause such side effects and, thus, may beused alone or in combination with other agents (e.g., cyclosporin and/orFK506) to treat or prevent rejection of transplanted tissues or organsand/or graft vs. host disease. Also, inhibitors of the voltage gatedKv1.3 potassium channel have been shown to be especially effective insuppressing effector memory T cells and, thus, the methods of presentinvention may be particularly effective in preventing or treatingdiseases that are associated with effector memory T cells, such as; boneresorption and periodontal disease, psoriasis, rheumatoid arthritis,type-1 diabetes mellitus and multiple sclerosis. In addition to T cellmediated diseases, the Kv1.3 channel has been determined to regulateenergy homeostasis, body weight and peripheral insulin sensitivity.Thus, the methods of the present invention may be used to treat otherdiseases and disorders that involve abnormal homeostasis, body weightand peripheral insulin sensitivity by inhibiting Kv1.3 channels on cellmembranes, such other diseases and disorders include but are notnecessarily limited to bone resorption in periodontal disease, Type 2diabetes, metabolic syndrome and obesity. Additionally, for MultipleSclerosis in particular, the current therapy with interferon-beta andcopaxone only benefits about 60% of patients. The appearance ofneutralizing antibodies in around 40% of patients treated withinterferon-beta makes interferon-beta treatment less effective over timein the responsive patients. Thus, the 5-Phenoxyalkoxypsoralens disclosedherein may provide substantial improvements in the treatment of MS.

Still further in accordance with the present invention, there areprovided methods for causing a desired inhibition of a first type ofpotassium channel (e.g., Kv1.3 channels) while not causing undesiredinhibition of a second type of potassium channel (e.g., Kv1.5 channels)in a human or animal subject. Such methods generally comprise the stepof administering to the human or animal subject a compound of GeneralFormula I in an amount and form that a) causes the desired inhibition ofpotassium channels of the first type but b) does not cause the undesiredinhibition of potassium channels of the second type. The “desiredinhibition of a first type of potassium channel” can be, for example,any inhibition of any type of potassium channel that causes an intendedtherapeutic or preventative effect, such as inhibition of Kv1.3potassium channels to treat or prevent a T cell mediated disorder in thehuman or animal subject. The “undesired inhibition of a second type ofpotassium channel” can be, for example, any inhibition of any type ofpotassium channel that causes a side effect, untoward effect or anyeffect other than the desired therapeutic or preventative effect, suchas the inhibition of Kv1.5 potassium channels in a way that causes aproarrhythmic effect or increases the potential for cardiac arrhythmiain the human or animal subject.

Still further in accordance with the present invention, there areprovided methods for inhibiting potassium channels in vitro bycontacting cells with one or more compounds of General Formula I. Suchmethods may be useful in pharmacologic research and/or for screening ofdrug candidates. Specific compounds of General Formula I may be selectedfor use in these methods on the basis of their relative inhibitoryselectivity for certain type(s) of potassium channels over other type(s)of potassium channels.

Still further aspects, objects and advantages of the invention willbecome apparent to persons of skill in the art upon reading andunderstanding of the detailed descriptions of the preferred embodimentsset forth herebelow.

DETAILED DESCRIPTION AND EXAMPLES

The following detailed description and the accompanying drawings areintended to describe some, but not necessarily all, examples orembodiments of the invention only and does not limit the scope of theinvention in any way.

Set forth herebelow are some examples of substituted5-phenoxyalkoxypsoralens of the present invention that inhibit the Kv1.3channel and suppress the proliferation of effector memory T cells in thelow nanomolar concentrations.

Example 1 5-(4-Phenoxybutoxy)psoralen (PAP 1)4-(4-Phenoxybutoxy)-7H-furo[3,2-g][1]benzopyran-7-on

700 mg (3.462 mmol) of 5-hydroxypsoralen (crystallized) and 600 mg(3.462 mmol) of 4-phenoxybutyl bromide was refluxed in 30 ml of2-butanone in the presence of an excess (2 g) of anhydrous potassiumcarbonate and catalytic amounts of potassium iodide for 24 hours. Theprogress of the reaction was monitored by thin layer chromatography.After 24 hours the reaction mixture was concentrated under reducedpressure. The oily residue was cooled and diluted with water. Theaqueous solution was then acidified with concentrated hydrochloric acidto pH 1. The slurry was stirred for 15-20 min and extracted with 3×100ml of dichloromethane. The dichloromethane layer was extracted with 25ml of 1% sodium hydroxide to separate the un-reacted 5-hydroxypsoralen.The dichloromethane layer was washed with 30 ml of 2% hydrochloric acid,dried over anhydrous sodium sulfate and concentrated. The solid residuewas dissolved in a methanol-acetone mixture, treated with charcoal andre-crystallized from a methanol-acetone (80:20) mixture.

Yield: 733.6 mg (60.48%) Melting point: 104° C. ¹H-NMR (500 MHz, CDCl₃):δ [ppm]=8.13 (d, 1H, ³J=9.7 Hz, 3-H), 7.59 (d,1H, ³J=2.0 Hz, 2′-H), 7.30(m, 5H, 5-OCH₂CH₂CH₂CH₂OC₆ H ₅), 7.15 (s, 1H, 8-H), 6.91 (d, 1H, ³J=2.0Hz, 3′-H), 6.25 (d, 1H, ³J=9.8 Hz, 4-H), 4.56 (t, 2H, ³J=6.14 Hz, 5-OCH₂CH₂CH₂CH₂OC₆H₅), 4.09 (t, 2H, ³J=5.80 Hz, 5-OCH₂CH₂CH₂CH ₂OC₆H₅), 2.09(m, 4H, ³J=4.21 Hz, 5-OCH₂CH ₂CH ₂CH₂OC₆H₅). ¹³C-NMR (DMSO-d₆, 75 MHz):δ [ppm]=25.26 and 26.18 (5-O—CH₂(CH₂)₂CH₂—O—C₆H₅); 66.91 and 72.29(5-O—CH₂(CH₂)₂ CH₂—O—C₆H₅); 93.18 (C-8); 105.62 (C-4′); 105.98 (C-4a);112.29 (C-3); 112.92 (C-6); 114.39 (C-3″ and C-5″); 120.39 (C-4″);129.41 (C-2″ and C-6″); 139.44 (C-4); 145.89 (C-5′); 148.72 (C-5);152.11 (C-8a); 157.63 (C-1″); 158.48 (C-7); 160.07 (C-2). MS (70 eV) m/z: 350 (20%, M⁺), 202 (9%, [M-C₁₀H₁₂O]⁺), 201 (5%), 174 (13%, [202-CO]⁺),173 (4%), 150 (11%), 149 (100%), 145 (8%), 107 (100%, [149-C₃H₆]⁺), 94(9%, C₆H₆O), 89 (4%), 77 (37%, C₆H₅), 65 (6%, C₅H₅). Combustionanalysis: (FW: 350.37) % C, 71.92; % H, 5.08. (Calc. % C, 71.99; % H,5.18)

Example 2 5-(3-Phenoxypropoxy)psoralen (PAP 3)4-(3-Phenoxypropoxy)-7H-furo[3,2-g][1]benzopyran-7-on

700 mg (3.5 mmol) of 5-hydroxypsoralen and 750 mg (3.5 mmol) of3-phenoxypropyl bromide were refluxed in 30 ml of 2-butanone in thepresence of an excess of anhydrous potassium carbonate (3.0 g) andcatalytic amounts of potassium iodide for 36 hours. The progress of thereaction was monitored by thin layer chromatography. After 36 hours thereaction mixture was concentrated under reduced pressure. The oilyresidue was cooled and diluted with water. The aqueous solution was thenacidified with concentrated hydrochloric acid to pH 1. The slurry wasstirred for 15-20 min and extracted with 3×30 ml of dichloromethane. Thedichloromethane layer was extracted with 25 ml of 1% sodium hydroxide toseparate the un-reacted 5-hydroxypsoralen. The dichloromethane layer waswashed with 30 ml of 2% hydrochloric acid, dried over anhydrous sodiumsulfate and concentrated. The resulting oily residue was dissolved inmethanol, treated with charcoal and re-crystallized from amethanol-ethyl acetate (10:90) mixture.

Yield: 390 mg (33.48%). Melting point: 108.4° C. ¹H-NMR (500 MHz,CDCl₃): δ [ppm]=8.13 (d, 1H, ³J=9.8 Hz, 3-H), 7.59 (d, 1H, ³J=2.3 Hz,2′-H), 7.31 (t, 3H, 3″-H, 4″-H, 5″-H), 7.16 (s, 1H, 8-H), 6.99 (d, 1H,³J=2.4 Hz, 3′-H), 6.93 (d, 2H, 2″-H, 6″-H), 6.24 (d, 1H, ³J=9.5 Hz,4-H), 4.66 (t, 2H, ³J=5.9 Hz, 5-OCH ₂CH₂CH₂OC₆H₅), 4.26 (t, 2H, ³J=6.0Hz, 5-OCH₂CH₂CH ₂OC₆H₅), 2.38 (p, 2H, ³J=6.0 Hz, 5-OCH₂CH ₂CH₂OC₆H₅). MS(70 eV) m/z: 336 (91%, M⁺), 203 (7%), 202 (57%, [M-C₉H₁₀O]⁺), 201 (11%),174 (16%, [202-CO]⁺), 173 (11%), 145 (14%), 135 (90%), 134 (9%), 108(8%), 107 (100%), 95 (8%), 89 (9%), 77 (62%, C₆H₅), 65 (9%, C₅H₅).Combustion analysis: (FW: 336.35) % C, 71.09; % H, 4.74. (Calc. % C,71.42; % H, 4.79)

Example 3 5-(2-Benzyloxyethoxy)psoralen (PAP 5)4-(2-Benzyloxyethoxy)-7H-furo[3,2-g][1]benzopyran-7-on

600 mg (2.967 mmol) of 5-hydroxypsoralen and 1.0 g (4.649 mmol) ofbenzyl-2-bromoethyl ether were refluxed in 30 ml of 2-butanone in thepresence of an excess of anhydrous potassium carbonate (2.0 g) andcatalytic amounts of potassium iodide for 16 hours. The progress of thereaction was monitored by thin layer chromatography. After 16 hours thereaction mixture was concentrated under reduced pressure. The oilyresidue was cooled and diluted with water. The aqueous solution was thenacidified with concentrated hydrochloric acid to pH 1. The slurry wasstirred for 15-20 min and extracted with 3×50 ml of dichloromethane. Thedichloromethane layer was extracted with 25 ml of 1% sodium hydroxide toseparate the un-reacted 5-hydroxypsoralen. The dichloromethane layer waswashed with 30 ml of 2% hydrochloric acid, dried over anhydrous sodiumsulfate and concentrated. The resulting oily residue was dissolved inmethanol, treated with charcoal and re-crystallized from 70% methanol.

Yield: 123 mg (12.33%) Melting point: 90.9° C. ¹H-NMR (500 MHz, CDCl₃):δ [ppm]=8.19 (d, 1H, ³J=9.7 Hz, 3-H), 7.59 (d, 1H, ³J=2.2 Hz, 2′-H),7.37 (m, 5H, 5-OCH₂CH₂OCH₂C₆ H ₅), 7.19(s, 1H, 8-H), 6.95 (d, 1H, ³J=2.0Hz, 3′-H), 6.25 (d, 1H, ³J=9.7 Hz, 4-H), 4.64 (s, 2H, 5-OCH₂CH₂OCH₂C₆H₅), 4.58 (t, 2H, ³J=4.62 Hz, 5-OCH ₂CH₂OCH₂C₆H₅), 3.88 (t, 2H,³J=4.56 Hz, 5-OCH₂CH ₂OCH₂C₆H₅). MS (70 eV) m/z: 336 (35%, M⁺), 105(5%), 91 (100%, [C₇H₇]⁺). Combustion analysis: (FW: 336.35) % C, 70.65;% H, 4.73. (Calc. % C, 71.42, % H 4.79)

Example 4 5-(4-Benzyloxybutoxy)psoralen (PAP 6)4-(4-Benzyloxybutoxy)-7H-furo[3,2-g][1]benzopyran-7-on

700 mg (3.5 mmol) of 5-hydroxypsoralen and 850.5 mg (3.5 mmol) ofbenzyl-4-bromobutyl ether was refluxed in 30 ml of 2-butanone in thepresence of an excess of anhydrous potassium carbonate (2.0 g) andcatalytic amounts of potassium iodide for 24 hours. The progress of thereaction was monitored by thin layer chromatography. After 24 hours thereaction mixture was concentrated under reduced pressure. The oilyresidue was cooled and diluted with water. The aqueous solution was thenacidified with concentrated hydrochloric acid to pH 1. The slurry wasstirred for 15-20 min and extracted with 3×50 ml of dichloromethane. Thedichloromethane layer was extracted with 25 ml of 1% sodium hydroxide toseparate the un-reacted 5-hydroxypsoralen. The dichloromethane layer waswashed with 30 ml of 2% hydrochloric acid, dried over anhydrous sodiumsulfate and concentrated. The oily residue was dissolved in methanol,treated with charcoal and re-crystallized from 80% methanol.

Yield: 171 mg (13.41%) Melting point: 78.4° C. ¹H-NMR (500 MHz, CDCl₃):δ [ppm]=8.14 (d, 1H, ³J=9.8 Hz, 3-H), 7.55 (d, 1H, ³J=2.5 Hz, 2′-H),7.34 (m, 5H, 5-OCH₂CH₂CH₂CH₂OCH₂C₆ H ₅), 7.13 (s, 1H, 8-H), 6.91 (d, 1H,³J=2.4 Hz, 3′-H), 6.25 (d, 1H, ³J=9.8 Hz, 4-H), 4.54 (s, 2H,5-OCH₂CH₂CH₂CH₂OCH ₂C₆H₅), 4.49 (t, 2H, ³J=6.5 Hz, 5-OCH₂CH₂CH₂CH₂OCH₂C₆H₅), 3.59 (t, 2H, ³J=6.1 Hz, 5-OCH₂CH₂CH₂CH ₂OCH₂C₆H₅),2.00 (p, 2H, ³J=6.9 Hz, 5-OCH₂CH ₂CH₂CH₂OCH₂C₆H₅), 1.87 (p, 2H, ³J=6.8Hz, 5-OCH₂CH₂CH ₂OCH₂ C₆H₅). MS (70 eV) m/z: 364 (37%, M⁺), 292 (10%),202 (7%, [M-C₁₁H₁₄O]⁺), 174 (6%, [202-CO]⁺), 163 (12%), 91 (100%, C₇H₇),71 (8%). Combustion analysis: (FW: 364.40) % C, 72.36; % H, 5.46. (Calc.% C, 72.51; % H, 5.53)

Example 5 5-(3-Benzyloxypropoxy)psoralen (PAP 7)4-(3-Benzyloxypropoxy)-7H-furo[3,2-g][1]benzopyran-7-on

1.0 g (4.946 mmol) of 5-hydroxypsoralen and 1.36 g (5.936 mmol) ofbenzyl-3-bromopropyl ether were refluxed in 30 ml of 2-butanone in thepresence of an excess of anhydrous potassium carbonate (3.4 g) andcatalytic amounts of potassium iodide for 24 hours. The progress of thereaction was monitored by thin layer chromatography. After 24 hours thereaction mixture was concentrated under reduced pressure. The oilyresidue was cooled and diluted with water. The aqueous solution was thenacidified with concentrated hydrochloric acid to pH 1. The slurry wasstirred for 15-20 min and extracted with 3×50 ml of dichloromethane. Thedichloromethane layer was extracted with 25 ml of 1% sodium hydroxide toseparate the un-reacted 5-hydroxypsoralen. The dichloromethane layer waswashed with 30 ml of 2% hydrochloric acid solution, dried over anhydroussodium sulfate and concentrated. The resulting oily residue wasdissolved in methanol, treated with charcoal and re-crystallized from70% methanol-water mixture.

Yield: 700 mg (40.39%) Melting point: 75.2° C. ¹H-NMR (500 MHz, CDCl₃):δ [ppm]=8.06 (d, 1H, ³J=9.7 Hz, 3-H), 7.57 (d, 1H, ³J=2.2 Hz, 2′-H),7.29 (m, 5H, ³J=6.3 Hz, 5-OCH₂CH₂CH₂OCH₂C₆ H ₅), 7.15 (s, 1H, 8-H), 6.98(d, 1H, ³J=2.2 Hz, 3′-H), 6.21 (d, 1H, ³J=9.8 Hz, 4-H), 4.58 (t, 2H,³J=6.1 Hz, 5-OCH ₂CH₂CH₂OCH₂C₆H₅), 4.55 (s, 2H, 5-OCH₂CH₂CH₂OCH ₂C₆H₅),3.73 (t, 2H, ³J=5.7 Hz, 5-OCH₂CH₂CH ₂OCH₂C₆H₅), 2.18 (p, 2H, ³J=6.1 Hz,5-OCH₂CH ₂CH₂OCH₂ C₆H₅). MS (70 eV) m/z: 350 (25%, M⁺), 202 (9%,[M-C₁₀H₁₂O]⁺), 174 (5%, [202-CO]⁺), 91 (100%, [C₇H₇]⁺). Combustionanalysis: (FW: 350.37) % C, 71.64, % H 5.34. (Calc. % C, 71.99; % H,5.18)

Example 6 5-(4-Chlorobutoxy)psoralen (I 1)4-(4-Chlorobutoxy)-7H-furo[3,2-g][1]benzopyran-7-on

817 mg (4.041 mmol) of 5-hydroxypsoralen and 1.413 g (6.47 mmol) of4-chlorobutyl iodide were refluxed in 80 ml of acetone in the presenceof an excess of (3.0 g) anhydrous potassium carbonate for 30 hours. Theprogress of the reaction was monitored by thin layer chromatography.After 30 hours the reaction mixture was concentrated under reducedpressure and distilled off the solvent almost completely. The oilyresidue was cooled and diluted with water. The aqueous solution was thenacidified with concentrated hydrochloric acid to pH 1. The slurry wasstirred for 15-20 min and extracted with 3×100 ml of dichloromethane.The dichloromethane layer was extracted with 1×25 ml of 1% sodiumhydroxide to separate trace amounts of un-reacted 5-hydroxypsoralen. Thedichloromethane layer was washed with 30 ml of 2% hydrochloric acid andfurther washed with water to neutral pH. The dichloromethane layer wasdried over anhydrous sodium sulfate and concentrated to dryness. Theresulting residue was then suspended in petroleum ether and filtered towash out the excess 4-chlorobutyl iodide. The resulting5-(4-chlorobutoxy)psoralen was used for the synthesis of variousderivatives without further purification.

Yield: 1.10 g (92.98%) Melting point: 115.4-115.6° C. ¹H-NMR (500 MHz,CDCl₃): δ [ppm]=8.15 (d, 1H, ³J=9.75 Hz, 3-H), 7.60 (d, 1H, ³J=2.62 Hz,2′-H), 7.17(s, 1H, 8-H), 6.95 (d, 1H, ³J=2.15 Hz, 3′-H), 6.29 (d, 1H,³J=9.79 Hz, 4-H), 4.52 (t, 2H, ³J=5.44 Hz, 5-OCH ₂CH₂CH₂CH₂Cl), 3.68 (t,2H, ³J=5.89 Hz, 5-OCH₂CH₂CH₂CH ₂Cl), 2.08 (p, 4H, ³J=3.06 Hz, 5-OCH₂CH₂CH ₂CH₂Cl).

Example 7 5-(4-{2″-Methoxy-4″-nitrophenoxy}butoxy)psoralen (PAP 10)4-(4-{2″-Methoxy-4″-nitrophenoxy}butoxy)-7H-furo[3,2-g][1]benzopyran-7-on

500 mg (1.708 mmol) of 5-(4-chlorobutoxy)psoralen, 741.41 mg (4.946mmol) of sodium iodide were refluxed in 15 ml of anhydrous acetonitrilefor 60 min to obtain the iodo derivative. To this solution were added837 mg (4.946 mmol) of 4-nitroguaicol, an excess (3.0 g) of anhydrouspotassium carbonate, 10 ml of anhydrous acetonitrile and the resultingmixture was refluxed for 72 hours. The progress of the reaction wasmonitored by thin layer chromatography. After 72 hours the reactionmixture was concentrated under reduced pressure. The residue was cooledand diluted with water. The aqueous solution was then acidified withconcentrated hydrochloric acid to pH 1. The slurry was stirred for 15-20min and extracted with 3×50 ml of dichloromethane. The dichloromethanelayer was extracted with 2×35 ml of 1% sodium hydroxide to separate theexcess of 4-nitroguaicol. The dichloromethane layer was washed with 30ml of 2% hydrochloric acid, dried over anhydrous sodium sulfate andconcentrated. The resulting solid was dissolved in methanol-acetonemixture, treated with charcoal and re-crystallized from amethanol-acetone (80:20) mixture.

Yield: 381.9 mg (52.56%) Melting point: 170.5° C. ¹H-NMR (500 MHz,CDCl₃): δ [ppm]=8.15 (d, 1H, ³J=9.8 Hz, 3-H), 7.91 (d, 1H, ⁴J=2.6 Hz,3″-H), 7.75 (dd, 1H, ³J=2.65 Hz, 5″-H), 7.60 (d, 1H, ³J=2.2 Hz, 2′-H),7.16 (s, 1H, 8-H), 6.98 (d, 1H, ³J=2.4 Hz, 3′-H), 6.93 (d, 1H, ³J=2.2Hz, 6″-H), 6.26 (d, 1H, ³J=9.7 Hz, 4-H), 4.59 (t, 2H, ³J=6.0 Hz, 5-OCH₂CH₂CH₂CH₂OC₆H₃[4-NO₂-2-CH₃O]), 4.23 (t, 2H, ³J=5.7 Hz, 5-OCH₂CH₂CH₂CH₂OC₆H₃[4-NO₂-2-CH₃O]), 3.915 (s, 3H, 2″-OCH₃), 2.14 (m, 4H, 5-OCH₂CH ₂CH₂CH₂OC₆H₃[4-NO₂-2-CH₃O]).

Example 8 5-(4-{4″-Methyl-2″-nitrophenoxy}butoxy)psoralen (PAP 11)4-(4-{4″-Methyl-2″-nitrophenoxy}butoxy)-7H-furo[3,2-g][1]benzopyran-7-on

500 mg (1.708 mmol) of 5-(4-chlorobutoxy)psoralen, and 741 mg (4.946mmol) of sodium iodide were refluxed in 15 ml of anhydrous acetonitrilefor 60 min to obtain the iodo derivative. To this solution were added523.2 mg (3.416 mmol) of 2-nitro-p-cresol, an excess of anhydrouspotassium carbonate (4.0 g), 10 ml anhydrous acetonitrile and theresulting mixture was refluxed for 69 hours. The progress of thereaction was monitored by thin layer chromatography. After 69 hours thereaction mixture was concentrated under reduced pressure. The residuewas cooled and diluted with water. The aqueous solution was thenacidified with concentrated hydrochloric acid to pH 1. The slurry wasstirred for 15-20 min and extracted with 3×50 ml of dichloromethane. Thedichloromethane layer was extracted with 2×30 ml of 1% sodium hydroxideto separate the excess of 2-nitro-p-cresol. The dichloromethane layerwas washed with 30 ml of 2% hydrochloric acid, dried over anhydroussodium sulfate and concentrated. The resulting residue was dissolved inmethanol-acetone mixture, treated with charcoal and re-crystallized froma methanol-acetone (80:20) mixture.

Yield: 447.2 mg (63.95%) Melting point: 124.5° C. ¹H-NMR (500 MHz,CDCl₃): δ [ppm]=8.14 (d, 1H, ³J=9.7 Hz, 3-H), 7.63 (d, 1H, ⁴J=1.8 Hz,3″-H), 7.59 (d, 1H, ³J=2.4 Hz, 2′-H), 7.31 (d, 1H, ³J=8.2 Hz, 5″-H) 7.14(s, 1H, 8-H), 6.98 (d, 1H, ³J=2.5 Hz, 3′-H), 6.96 (d, 1H, ³J=8.76 Hz,6″-H), 6.26 (d, 1H, ³J=9.8 Hz, 4-H), 4.56 (t, 2H, ³J=5.7 Hz, 5-OCH₂CH₂CH₂CH₂OC₆H₃[4-CH₃-2-NO₂]), 4.17 (t, 2H, ³J=6.0 Hz, 5-OCH₂CH₂CH₂CH₂OC₆H₃[4-CH₃-2-NO₂]), 2.34 (s, 3H, 4″-CH₃), 2.05 (m, 4H, ³J=4.216 Hz,5-OCH₂CH ₂CH ₂CH₂OC₆H₃[4-CH₃-2-NO₂]).

Example 9 5-(4-{2″-Nitrophenoxy}butoxy)psoralen (PAP 12)4-(4-{2″-Nitrophenoxy}butoxy)-7H-furo[3,2-g][1]benzopyran-7-on

500 mg (1.708 mmol) of 5-(4-chlorobutoxy)psoralen, and 512 mg (3.416mmol) of sodium iodide were refluxed in 15 ml of anhydrous acetonitrilefor 60 min to obtain the iodo derivative. To this solution were added475 mg (3.416 mmol) of 2-nitrophenol, an excess (4.0 g) of anhydrouspotassium carbonate, 15 ml of anhydrous acetonitrile and the resultingmixture was refluxed for 29 hours. The progress of the reaction wasmonitored by thin layer chromatography. After 29 hours the reactionmixture was concentrated under reduced pressure. The residue was cooledand diluted with water. The aqueous solution was then acidified withconcentrated hydrochloric acid to pH 1. The slurry was stirred for 15-20min and extracted with 3×50 ml of dichloromethane. The dichloromethanelayer was extracted with 2×20 ml of 1% sodium hydroxide solution toseparate the excess of 2-nitrophenol. The dichloromethane layer waswashed with 30 ml of 2% hydrochloric acid solution, dried over anhydroussodium sulfate and concentrated. The solid residue obtained wasdissolved in methanol-acetone mixture, treated with charcoal andre-crystallized from a methanol-acetone (80:20) mixture.

Yield: 380.3 mg (56.32%) Melting point: 121.6-121.8° C. ¹H-NMR (500 MHz,CDCl₃): δ [ppm]=8.14 (d, 1H, ³J=9.7 Hz, 3-H), 7.82-7.86 (overlapping dd,2H, ⁴J=1.6 Hz, ³J=8.3 Hz, ³J=7.91 Hz, 3″-H, 6″-H), 7.60 (d, 1H, ³J=2.5Hz, 2′-H), 7.52-7.55 (t, 2H, ³J=7.57 Hz, ⁴J=1.0 Hz, 3″-H, 4″-H), 7.15(s, 1H, 8-H), 6.99 (d, 1H, ³J=2.35 Hz, 3′-H), 6.26 (d, 1H, ³J=9.7 Hz,4-H), 4.57 (t, 2H, ³J=5.8 Hz, 5-OCH ₂CH₂CH₂CH₂OC₆H₄[2-NO₂]), 4.23 (t,2H, ³J=2.74 Hz, 5-OCH₂CH₂CH₂CH ₂O C₆H₄[2-NO₂]), 2.09-2.16 (m, 4H,5-OCH₂CH ₂CH ₂CH₂OC₆H₄[2-NO₂]).

Example 10 5-(4-{3″-Nitrophenoxy}butoxy)psoralen (PAP 13)4-(4-{3″-Nitrophenoxy}butoxy)-7H-furo[3,2-g][1]benzopyran-7-on

500 mg (1.708 mmol) of 5-(4-chlorobutoxy)psoralen and 512 mg (3.416mmol) of sodium iodide were refluxed in 15 ml of anhydrous acetonitrilefor 60 min to obtain the iodo derivative. To this solution were added475 mg (3.416 mmol) of 3-nitrophenol, an excess (4.0 g) of anhydrouspotassium carbonate, 15 ml anhydrous acetonitrile and the resultingmixture was refluxed for 29 hours. The progress of the reaction wasmonitored by thin layer chromatography. After 29 hours the reactionmixture was concentrated under reduced pressure. The residue was cooledand diluted with water. The aqueous solution was then acidified withconcentrated hydrochloric acid to pH 1. The slurry was stirred for 15-20min and extracted with 3×50 ml of dichloromethane. The dichloromethanelayer was extracted with 2×20 ml of 1% sodium hydroxide to separate theexcess of 3-nitrophenol. The dichloromethane layer was washed with 30 mlof 2% hydrochloric acid, dried over anhydrous sodium sulfate andconcentrated. The resulting residue was dissolved in methanol-acetonemixture, treated with charcoal and re-crystallized from amethanol-acetone (80:20) mixture.

Yield: 286.4 mg (42.41%) Melting point: 140.3° C. ¹H-NMR (500 MHz,CDCl₃): δ [ppm]=8.15 (d, 1H, ³J=9.7 Hz, 3-H), 7.84 (dd, 1H, ³J=8.1 Hz,⁴J=1.6 Hz, 4″-H), 7.61 (d, 1H, ³J=2.3 Hz, 2′-H), 7.42 (t, 1H, ³J=8.3 Hz,5″-H), 7.41 (t, 1H, ⁴J=2.2 Hz, 2″-H), 7.22 (dd, 1H, ³J=8.1 Hz, ⁴J=2.3Hz, 6″-H) 7.16 (s, 1H, 8-H), 6.97 (d, 1H, ³J=2.2 Hz, 3′-H), 6.27 (d, 1H,³J=9.8 Hz, 4-H), 4.56 (t, 2H, ³J=5.8 Hz, 5-OCH ₂CH₂CH₂CH₂OC₆H₄[3-NO₂]),4.16 (t, 2H, ³J=5.6 Hz, 5-OCH₂CH₂CH₂ CH ₂OC₆H₄[3-NO₂]), 2.12 (m, 4H,5-OCH₂CH ₂CH ₂CH₂OC₆H₄[3-NO₂]).

Example 11 5-(4-{2″,4″-Dinitrophenoxy}butoxy)psoralen (PAP 14)4-(4-{2″,4″-Dinitrophenoxy}butoxy)-7H-furo[3,2-g][1]benzopyran-7-on

500 mg (1.708 mmol) of 5-(4-chlorobutoxy)psoralen, 512 mg (3.416 mmol)of sodium iodide and 629 mg (3.416 mmol) of 2,4-dinitrophenol wererefluxed in 30 ml of anhydrous acetonitrile in the presence of an excess(3 g) of anhydrous potassium carbonate for 50 hours. The progress of thereaction was monitored by thin layer chromatography. After 50 hours thereaction mixture was concentrated under reduced pressure. The residuewas cooled and diluted with water. The aqueous solution was thenacidified with concentrated hydrochloric acid to pH 1. The slurry wasstirred for 15-20 min and extracted with 3×50 ml of dichloromethane. Thedichloromethane layer was extracted with 2×35 ml of 1% sodium hydroxideto separate the excess of 2,4-dinitrophenol. The dichloromethane layerwas washed with 30 ml of 2% hydrochloric acid, dried over anhydroussodium sulfate and concentrated. The solid residue obtained wasdissolved in methanol-acetone mixture, treated with charcoal andre-crystallized from a methanol-acetone (80:20) mixture.

Yield: 82.4 mg (10.96%) Melting point: 134.2° C. ¹H-NMR (500 MHz,CDCl₃): δ [ppm]=8.78 (d, 1H, ⁴J=2.8 Hz, 3″-H), 8.45 (dd, 1H, ³J=9.0 Hz,⁴J=2.8 Hz, 5″-H), 8.15 (d, 1H, ³J=9.7 Hz, 3-H), 7.61 (d, 1H, ³J=2.0 Hz,2′-H), 7.22 (d, 1H, ³J=9.5 Hz, 6″-H),_(—)7.17 (s, 1H, 8-H), 6.98 (d, 1H,³J=2.1 Hz, 3′-H), 6.29 (d, 1H, ³J=9.8 Hz, 4-H), 4.57 (t, 2H, ³J=5.3 Hz,5-OCH ₂CH₂CH₂CH₂OC₆H₃[2,4-(NO₂)₂]), 4.36 (t, 2H, ³J=5.1 Hz,5-OCH₂CH₂CH₂CH ₂OC₆H₃[2,4-(NO₂)₂]), 2.2 (m, 4H, 5-OCH₂CH ₂CH₂CH₂OC₆H₃[2,4-(NO₂)₂]).

The following Examples 12-47 describe compounds that may be synthesizedby methods that are similar to those described above with respect toExamples 1-11 and, thus, only physical data is being provided for thecompounds of Examples 12-47.

Example 12 5-(4-[4-Methoxyphenoxy]butoxy)psoralen (AS67)4-(4-[4-Methoxyphenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 111.5° C. Combustion analysis: C₂₂H₂₀O₆ (380.4)calculated: C 69.46 H 5.30 found: C 69.52 H 5.39

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=1.91-1.99 (m, 4H, 5-O—CH₂(CH₂)₂CH₂—O—C₆H₄—OCH₃); 3.69 (s, 3H, —OCH ₃); 4.00 (t, 2H, ³J=5.8 Hz,5-O—CH₂(CH₂)₂CH ₂—O—C₆H₄—OCH₃); 4.57 (t, 2H, ³J=5.7 Hz, 5-O—CH₂(CH₂)₂CH₂—O—C₆H₄—OCH₃); 6.30 (d, 1H, ³J=9.8 Hz, H-3); 6.81-6.87 (m, 4H,5-O—CH₂(CH₂)₂CH₂—O—C₆ H ₄—OCH₃); 7.32-7.34 (m, 2H, H-8 and H-4′); 8.03(d, 1H, ³J=2.3 Hz, H-5′); 8.18 (d, 1H, ³J=9.8 Hz, H-4). ¹³C-NMR(DMSO-d₆, 75 MHz): δ/ppm (TMS)=25.30 and 26.18(5-O—CH₂(CH₂)₂CH₂—O—C₆H₅); 55.3 (—OCH₃); 67.49 and 72.29 (5-O—CH₂(CH₂)₂CH₂—O—C₆H₅); 93.17 (C-8); 105.61 (C-4′); 105.97 (C-4a); 112.27 (C-3);112.91 (C-6); 114.54 and 115.29 (C-2″, C-3″, C-5″ and C-6″); 139.42(C-4); 145.88 (C-5′); 148.71 (C-5); 152.10 (C-8a); 152.47 and 153.25(C-1″ and C-4″); 157.62 (C-7); 160.06 (C-2). IR (KBr): ν/cm⁻¹=3126,2958, 1722, 1626, 1508, 1233, 1130. MS (EI): m/z (%)=380 M⁺ (14), 257(8), 215 (7), 202 [M-C₁₁H₁₄O₂]⁺ (5), 179 [C₁₁H₁₅O₂]⁺ (69), 145 (6), 137[CH₃—O—C₆H₄O—CH₂]⁺ (100), 109 (29), 107 [C₆H₅O—CH₂]⁺ (18), 77 [C₆H₅]⁺(23), 55 [C₄H₇]⁺ (61), 41 (15).

Example 13 5-(4-[3-Methoxyphenoxy]butoxy)psoralen (AS68)4-(4-[3-Methoxyphenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 102.5° C. Combustion analysis: C₂₂H₂₀O₆ (380.4)calculated: C 69.46 H 5.30 found: C 68.89 H 5.38

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=1.91-1.99 (m, 4H, 5-O—CH₂(CH₂)₂CH₂—O—C₆H₄—OCH₃); 3.71 (s, 3H, —OCH ₃); 4.05 (t, 2H, ³J=5.4 Hz,5-O—CH₂(CH₂)₂CH ₂—O—C₆H₄—OCH₃); 4.58 (t, 2H, ³J=5.4 Hz, 5-O—CH₂(CH₂)₂—O—C₆H₄—OCH₃); 6.29 (d, 1H, ³J=9.8 Hz, H-3); 6.45-6.51 (m, 3H,H-2″, H-4″ and H-6″); 7.15 (t, 1H, ³J=8.14 Hz, H-5″); 7.33 (s, 2H, H-8and H-4′); 8.02 (d, 1H, ³J=1.9 Hz, H-5″); 8.18 (d, 1H, ³J=9.8 Hz, H-4).¹³C-NMR (DMSO-d₆, 75 MHz): δ/ppm (TMS)=25.21 and 26.17(5-O—CH₂(CH₂)₂CH₂—O—C₆H₄—OCH₃); 54.98 (—OCH₃); 67.04 and 72.24(5-O—CH₂(CH₂)₂ CH₂—O—C₆H₄—OCH₃); 93.15 (C-8); 100.62 (C-5″); 105.61(C-4′); 105.95 (C-4a); 106.14 and 106.57 (C-4″ and C-6″); 112.25 (C-3);112.89 (C-6); 129.86 (C-2″); 139.42 (C-4); 145.86 (C-5′); 148.69 (C-5);152.09 (C-8a); 157.61 (C-7); 159.73 and 160.44 (C-1″ and C-3″); 160.05(C-2). IR (KBr): ν/cm⁻¹=3128, 2948, 1728, 1626, 1604, 1454, 1348, 1154.MS (EI): m/z (%)=380 M⁺ (14), 257 (8), 202 [M-C₁₁H₁₄O₂]⁺ (5), 179[C₁₁H₁₅O₂]⁺ (84), 145 (6), 137 [CH₃—O—C₆H₄O—CH₂]⁺ (100), 109 (14), 107[C₆H₅O—CH₂]⁺ (32), 77 [C₆H₅]⁺ (27), 55 [C₄H₇]⁺ (63), 41 (12).

Example 14 5-(4-[3,5-Dimethoxyphenoxy]butoxy)psoralen (AS69)4-(4-[3,5-Dimethoxyphenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 139° C. Combustion analysis: C₂₃H₂₂O₇ (410.43)calculated: C 67.31 H 5.40 found: C 66.92 H 5.60

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=1.93-1.97 (m, 4H, 5-O—CH₂(CH₂)₂CH₂—O—C₆H₃—(OCH₃)₂); 3.69 (s, 3H, —(OCH ₃)₂); 4.05 (t, 2H, ³J=5.4 Hz,5-O—CH₂(CH₂)₂CH ₂—O—C₆H₃—(OCH₃)₂); 4.58 (t, 2H, ³J=5.4 Hz, 5-O—CH₂(CH₂)₂CH₂—O—C₆H₃—(OCH₃)₂); 6.07 (s, 3H, H-2″, H-4″ and H-6″); 6.31 (d,1H, ³J=9.8 Hz, H-3); 7.34 (s, 2H, H-8 and H-4′); 8.03 (d, 1H, ³J=2.1 Hz,H-5′); 8.19 (d, 1H, ³J=9.8 Hz, H-4). ¹³C-NMR (DMSO-d₆, 75 MHz): δ/ppm(TMS)=25.15 and 26.18 (5-O—CH₂(CH₂)₂CH₂—O—C₆H₃—(OCH₃)₂); 55.05(—(OCH₃)₂); 67.10 and 72.20 (5-O—CH₂(CH₂)₂ CH₂—O—C₆H₃—(OCH₃)₂); 92.79(C-4″); 93.12 (C-8); 93.21 (C-2″ and C-6″); 105.61 (C-4′); 105.94(C-4a); 112.22 (C-3); 112.86 (C-6); 139.40 (C-4); 145.84 (C-5′); 148.68(C-5); 152.09 (C-8a); 157.61 (C-7); 160.05 (C-2); 160.34 (C-1″); 161.09(C-3″ and C-5″). IR (KBr): ν/cm⁻¹=3158, 2954, 1716, 1600, 1456, 1354,1152. MS (EI): m/z (%)=410 M⁺ (12), 209 [C₁₂H₁₇O₃]⁺ (100), 202[M-[C₁₂H₁₇O₃]⁺ (5), 167 [(CH₃—O)₂—C₆H₃O—CH₂]⁺ (75), 137[CH₃—O—C₆H₄O—CH₂]⁺ (34), 122 (15), 107 [C₆H₅O—CH₂]⁺ (10), 77 [C₆H₅]⁺(11), 55 [C₄H₇]⁺ (46), 41 (6).

Example 15 5-(4-[4-Nitrophenoxy]butoxy)psoralen (AS78)4-(4-[4-Nitrophenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 132° C. Combustion analysis: C₂₁H₁₇O₇ (395.34)calculated: C 63.80 H 4.33 N 3.54 found: C 63.79 H 4.46 N 3.60

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=1.99 (s, 4H, 5-O—CH₂(CH₂)₂CH₂—O—C₆H₄—NO₂); 4.05 (s, 2H, 5-O—CH₂(CH₂)₂CH ₂—O—C₆H₄—NO₂); 4.56 (s,2H, 5-O—CH ₂(CH₂)₂CH₂—O—C₆H₄—NO₂); 6.27 (d, 1H, ³J=9.8 Hz, H-3); 7.10(d, 2H, ³J=9.2 Hz, H-2″ and H-6″); 7.28 (s, 1H, H-8); 7.30 (d, 1H,³J=1.9 Hz, H-4′); 8.00 (d, 1H, ³J=2.1 Hz, H-5′); 8.15 (d, 1H, ³J=9.6 Hz,H-4); 8.16 (d, 2H, ³J=9.1 Hz, H-3″ and H-5″). ¹³C-NMR (DMSO-d₆, 75 MHz):δ/ppm (TMS)=24.95 and 25.96 (5-O—CH₂(CH₂)₂CH₂—O—C₆H₄—NO₂); 68.25 and72.04 (5-O—CH₂(CH₂)₂ CH₂—O—C₆H₄—NO₂); 93.07 (C-8); 105.56 (C-4″); 105.84(C-4a); 112.17 (C-3); 112.78 (C-6); 114.87 and 125.74 (C-2″, C-3″, C-5″and C-6″); 139.28 (C-4); 140.65 (C-4″); 145.80 (C-5′); 148.58 (C-5);152.03 (C-8a); 157.57 (C-7); 159.99 (C-2); 163.80 (C-1″). IR (KBr):ν/cm⁻¹=2960, 2881, 1728, 1593, 1498, 1455, 1327, 1270. MS (EI): m/z(%)=395 M⁺ (25), 202 [M-C₁₀H₁₄O₃N]⁺ (30), 194 [C₁₀H₁₂O₃N]⁺ (100), 174[202-CO]⁺ (26), 152 [O₂N—C₆H₄O—CH₂]⁺ (82), 133 (17), 106 (17), 89 (13),75 (12), 55 [C₄H₇]⁺ (84), 41 (11).

Example 16 5-(4-[4-Chlorphenoxy]butoxy)psoralen (AS84)4-(4-[4-Chlorphenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 142.5° C. Combustion analysis: C₂₁H₁₇ClO₅ (384.82)calculated: C 65.55 H 4.45 found: C 65.23 H 4.57

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=1.95-1.96 (m, 4H, 5-O—CH₂(CH₂)₂CH₂—O—C₆H₄—Cl); 4.05 (m, 2H, 5-O—CH₂(CH₂)₂CH ₂—O—C₆H₄—Cl); 4.55 (m,2H, 5-O—CH ₂(CH₂)₂CH₂—O—C₆H₄—Cl); 6.28 (d, 1H, ³J=9.8 Hz, H-3); 6.93 (d,2H, ³J=8.9 Hz, H-2″ and H-6″); 7.29 (d, 2H, ³J=8.9 Hz, H-3″ and H-5″);7.31 (s, 2H, H-8 and H-4′); 8.01 (d, 1H, ³J=2.0 Hz, H-5′); 8.15 (d, 1H,³J=9.8 Hz, H-4). ¹³C-NMR (DMSO-d₆, 75 MHz): δ/ppm (TMS)=25.12 and 26.08(5-O—CH₂(CH₂)₂CH₂—O—C₆H₄—Cl); 67.44 and 72.17 (5O—CH₂(CH₂)₂CH₂—O—C₆H₄—Cl); 93.10 (C-8); 105.59 (C-4′); 105.89 (C-4a); 112.21 (C-3);112.83 (C-6); 116.14 (C-2″ and C-6″); 124.08 (C-4″); 129.13 (C-3″ andC-5″); 139.34 (C-4); 145.83 (C-5′); 148.65 (C-5); 152.07 (C-8a); 157.32(C-7); 157.60 (C-1″); 160.03 (C-2). IR (KBr): ν/cm⁻¹=3090, 2929, 2882,1718, 1618, 1577, 1491, 1346, 1246. MS (EI): m/z (%)=384 M⁺(10), 202[M-C₁₀H₁₄ClO]⁺ (14), 183 [C₁₀H₁₂OCl]⁺(80), 174 [202-CO]⁺ (11), 141[Cl—C₆H₄O—CH₂]⁺ (100), 113 (18), 111 (23), 89 (7), 77 [C₆H₅]⁺ (9), 55[C₄H₇]⁺(72), 41 (5).

Example 17 5-(4-[4-Phenoxyphenoxy]butoxy)psoralen (AS85)4-(4-[4-Phenoxyphenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 137° C. Combustion analysis: C₂₇H₂₂O₆ (442.47)calculated: C 73.29 H 5.01 found: C 73.24 H 5.09

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=1.97 (s, 4H, 5O—CH₂(CH₂)₂CH₂—O—C₆H₄—O—C₆H₅); 4.05 (s, 2H, 5-O—CH₂(CH₂)₂CH ₂—O—C₆H₄—O—C₆H₅);4.57 (s, 2H, 5-O—CH ₂(CH₂)₂CH₂—O—C₆H₄—O—C₆H₅); 6.29 (d, 1H, ³J=9.7 Hz,H-3); 6.89-6.96 (m, 6H, —O—C₆ H ₄—O—C₆ H ₅); 7.06 (t, 1H, H-4′″);7.31-7.35 (m, 4H, H-8, H-4′ and —O—C₆ H ₄—O—C₆ H ₅); 8.02 (s, 1H, H-5′);8.17 (d, 1H, ³J=9.8 Hz, H-4). ¹³C-NMR (DMSO-d₆, 75 MHz): δ/ppm(TMS)=25.28 and 26.14 (5O—CH₂(CH₂)₂CH₂—O—C₆H₄—O—C₆H₅); 67.46 and 72.23(5O—CH₂(CH₂)₂ CH₂—O—C₆H₄—O—C₆H₅); 93.11 (C-8); 105.59 (C-4′); 105.91(C-4a); 112.22 (C-3); 112.85 (C-6); 139.36 (C-4); 145.83 (C-5′); 148.67(C-5); 152.07 (C-8a); 157.60 (C-7); 160.03 (C-2); 115.60, 117.23,120.57, 122.49, 129.78, 149.32, 154.85 and 157.92 (—O—C ₆H₄—O—C ₆H₅). IR(KBr): ν/cm⁻¹=3119, 2930, 1724, 1626, 1578, 1506, 1456, 1349, 1221. MS(EI): m/z (%)=442 M⁺ (25), 257 (16), 241 [C₆H₅—OC₁₀H₁₂O]⁺ (100), 215(12), 199 [C₆H₅—OC₈H₈O]⁺ (100), 186 [C₆H₅—OC₇H₅O]⁺ (100), 171 (12), 148(38), 129 (13), 115 (17), 93 (10), 77 [C₆H₅]⁺ (49), 55 [C₄H₇]⁺ (70), 41(7).

Example 18 5-(4-[4-Methylphenoxy]butoxy)psoralen (AS96)4-(4-[4-Methylphenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 128° C. Combustion analysis: C₂₂H₂₀O₅ (364.40)calculated: C 72.51 H 5.53 found: C 72.59 H 5.65

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=1.92-2.01 (m, 4H, 5O—CH₂(CH₂)₂CH₂—O—C₆H₄—CH₃); 2.22 (s, 3H, —CH₃); 4.02 (t, 2H, ³J=5.7 Hz,5—O—CH₂)₂CH ₂—O—C₆H₄—CH₃); 4.56 (t, 2H, ³J=5.6 Hz, 5-O—CH₂(CH₂)₂CH₂—O—C₆H₄—CH₃); 6.28 (d, 1H, ³J=9.8 Hz, H-3); 6.80 (d, 2H,³J=8.5 Hz, H-3″ and H-5″); 7.06 (d, 2H, ³J=8.4 Hz, H-2″ and H-6″); 7.31(s, 2H, H-8 and H-4′); 8.02 (d, 1H, ³J=2.1 Hz, H-5′); 8.15 (d, 1H,³J=9.8 Hz, H-4). ¹³C-NMR (DMSO-d₆, 75 MHz): δ/ppm (TMS)=19.97 (—CH₃);25.25 and 26.16 (5—O—CH₂(CH₂)₂CH₂—O—C₆H₄—CH₃); 66.96 and 72.21(5-O—CH₂(CH₂)₂ CH₂—O—C₆H₄—CH₃); 93.06 (C-8); 105.56 (C-4′); 105.87(C-4a); 112.16 (C-3); 112.79 (C-6); 114.19 (C-3″ and C-5″); 152.05(C-8a); 156.33 (C-1″); 157.57 (C-7); 160.01 (C-2). IR (KBr):ν/cm⁻¹=3091, 2915, 1717, 1619, 1576, 1509, 1456, 1346, 1244. MS (EI):m/z (%)=364 M⁺ (10), 202 [M-C₁₁H₁₃O]⁺ (5), 163 [C₁₁H₁₅O]⁺ (87), 121[CH₃—C₆H₄O—CH₂]⁺ (100), 91 [C₇H₇]⁺ (33), 65 (9), 55 [C₄H₇]⁺ (35), 41(4).

Example 19 5-(4-[4-Ethylphenoxy]butoxy)psoralen (AS106)4-(4-[4-Ethylphenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 104° C. Combustion analysis: C₂₃H₂₂O₅ (378.43)calculated: C 73.00 H 5.86 found: C 71.74 H 5.89

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=1.14 (t, 3H, ³J=7.6 Hz, —CH₂CH₃); 1.95-1.99 (m, 4H, 5-O—CH₂(CH ₂)₂CH₂—O—C₆H₄—CH₂CH₃); 2.52 (q, 2H,³J=7.6 Ha —CH ₂CH₃); 4.03 (t, 2H, ³J=5.7 Hz, 5-O—CH₂(CH₂)₂CH₂—O—C₆H₄—CH₂CH₃); 4.57 (t, 2H, ³J=5.7 Hz, 5-O—CH₂(CH₂)₂CH₂—O—C₆H₄—CH₂CH₃); 6.28 (d, 1H, ³J=9.8 Hz, H-3); 6.82 (d, 2H,³J=8.6 Hz, H-3″ and H-5″); 7.09 (d, 2H, ³J=8.5 Hz, H-2″ and H-6″); 7.33(s, 2H, H-8 and H-4′); 8.02 (d, 1H, ³J=2.3 Hz, H-5′); 8.18 (d, 1H,³J=9.8 Hz, H-4). ¹³C-NMR (DMSO-d₆, 75 MHz): δ/ppm (TMS)=15.82 (—CH₃);25.27 and 26.17 (5-O—CH₂(CH₂)₂CH₂—O—C₆H₄—C₂H₅); 27.20 (—CH₂CH₃); 66.98and 72.26 (5-O—CH₂(CH₂)₂ CH₂—O—C₆H₄—C₂H₅); 93.13 (C-8); 105.59 (C-4′);105.93 (C-4a); 112.22 (C-3); 112.87 (C-6); 114.22 (C-3″ and C-5″);128.51 (C-4″); 135.55 (C-2″ and C-6″); 139.38 (C-4); 145.84 (C-5′);148.68 (C-5); 152.08 (C-8a); 156.51 (C-1″); 157.60 (C-7); 160.03 (C-2).IR (KBr): ν/cm⁻¹=3088, 2928, 1720, 1618, 1576, 1512, 1456, 1346, 1250.MS (EI): m/z (%)=378 M⁺(9), 202 [M-C₁₂H₁₅O]⁺ (5), 177 [C₁₂H₁₇O]⁺ (92),135 [CH₃—CH₂C₆H₄O—CH₂]⁺ (100), 107 [C₈H₁₁]⁺ (26), 79 (22), 55 [C₄H₇]⁺(44).

Example 20 5-(4-[4-Fluorphenoxy]butoxy)psoralen (AS111)4-(4-[4-Fluorphenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 121° C. Combustion analysis: C₂₁H₁₇FO₅ (368.37)calculated: C 68.47 H 4.65 found: C 68.15 H 4.65

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=1.94-1.96 (m, 4H, 5-O—CH₂(CH₂)₂CH₂—O—C₆H₄—F); 4.01-4.05 (m, 2H, 5-O—CH₂(CH₂)₂CH ₂—O—C₆H₄—F);4.53-4.55 (m, 2H, 5-O—CH ₂(CH₂)₂CH₂—O—C₆H₄—F); 6.27 (d, 1H, ³J=9.8 Hz,H-3); 6.89-6.94 (m, 2H, 5-O—CH₂(CH₂)₂CH₂—O—C₆ H ₄—F); 7.30 (s, 2H, H-4′and H-8); 8.01 (d, 1H, ³J=2.0 Hz, H-5′); 8.14 (d, 1H, ³J=9.8 Hz, H-4).¹³C-NMR (DMSO-d₆, 75 MHz): δ/ppm (TMS)=25.20 and 26.10(5-O—CH₂(CH₂)₂CH₂—O—C₆H₄—F); 67.60 and 72.17 (5-O—CH₂(CH₂)₂CH₂—O—C₆H₄—F); 93.07 (C-8); 105.56 (C-4′); 105.87 (C-4a); 112.18 (C-3);112.80 (C-6); 115.53, 115.63 and 115.83 (C-2″, C-3″, C-5″ and C-6″);139.32 (C-4); 145.80 (C-5′); 148.63 (C-5); 152.05 (C-8a); 154.79 (C-5″);157.58 (C-7); 157.91 (C-1″); 160.02 (C-2). IR (KBr): ν/cm⁻¹=2947, 1722,1625, 1503, 1457, 1346, 1203. MS (EI): m/z (%)=368 M⁺ (11), 202[M-C₁₀H₁₄FO]⁺ (11), 174 [202-CO]⁺ (11), 167 [C₁₀H₁₂OF]⁺ (83), 125[F—C₆H₄O—CH₂]⁺ (100), 95 (23), 89 (5), 55 [C₄H₇]⁺ (46), 41 (3).

Example 21 5-(4-[3-Trifluormethylphenoxy]butoxy)psoralen (AS118)4-(4-[3-Trifluormethylphenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 118° C. Combustion analysis: C₂₂H₁₇F₃O₅ (418.37)calculated: C 63.16 H 4.10 found: C 63.19 H 4.09

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=1.98 (s, 4H, 5-O—CH₂(CH₂)₂CH₂—O—C₆H₄—CF₃); 4.15 (s, 2H, 5-O—CH₂(CH₂)₂CH ₂—O—C₆H₄—CF₃); 4.57 (s,2H, 5-O—CH ₂(CH₂)₂CH₂—O—C₆H₄—CF₃); 6.26 (d, 1H, ³J=9.8 Hz, H-3);7.18-7.32 (m, 5H, H-2″, H-4″, H-6″, H-8 and H-4′); 7.49 (t, 1H, ³J=7.93Hz, H-5″); 8.01 (d, 1H, ³J=2.3 Hz, H-5′) 8.15 (d, 1H, ³J=9.8 Hz, H-4).¹³C-NMR (DMSO-d₆, 75 MHz): δ/ppm (TMS)=25.05 and 26.04(5-O—CH₂(CH₂)₂CH₂—O—C₆H₄—CF₃); 67.56 and 72.10 (5-O—CH₂(CH₂)₂CH₂—O—C₆H₄—CF₃); 93.06 (C-8); 105.58 (C-4′); 105.84 (C-4a); 110.78,110.84, 116.86, 116.91 and 130.58 (5-O—CH₂(CH₂)₂CH₂—O—C ₆H₄—CF₃); 112.16(C-3); 112.78 (C-6); 118.64 (—CF₃); 139.30 (C-4); 145.78 (C-5′); 148.63(C-5); 152.06 (C-8a); 157.59 (C-7); 158.76 (C-1″); 160.00 (C-2). IR(KBr): ν/cm⁻¹=2960, 1724, 1626, 1590, 1456, 1348, 1328, 1130. MS (EI):m/z (%)=418 M⁺ (14), 217 (79), 202 [M-C₁₁H₁₄O₂]⁺ (19), 175 [C₁₂H₁₅O]⁺(100), 145 (37), 127 (7), 109 (14), 89 (6), 55 [C₄H₇]⁺ (75) 41 (4).

Example 22 5-(4-[1-Naphthyloxy]butoxy)psoralen (AS119)4-(4-[1-Naphthyloxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 119° C. Combustion analysis: C₂₅H₂₀O₅ (400.44)calculated: C 74.99 H 5.30 found: C 74.91 H 5.16

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=2.10 (s, 4H, 5-O—CH₂(CH₂)₂CH₂—O—C₁₀H₇); 4.25 (s, 2H, 5-O—CH₂(CH₂)₂CH ₂—O—C₁₀H₇); 4.63 (s, 2H,5-O—CH ₂(CH₂)₂CH₂—O—C₁₀H₇); 6.22 (d, 1H, ³J=9.8 Hz, H-3); 6.95 (d, 1H,³J=7.2 Hz, 5-O—CH₂(CH₂)₂CH₂—O—C₁₀ H ₇); 7.30-7.52 (m, 6H, H-8, H-4′ and5-O—CH₂(CH₂)₂CH₂—O—C₁₀ H ₇); 7.84 (d, 1H, ³J=8.1 Hz,5-O—CH₂(CH₂)₂CH₂—O—C₁₀ H ₇); 8.00 (d, 1H, ³J=2.2 Hz, H-5′); 8.08 (d, 1H,³J=8.3, 5-O—CH₂(CH₂)₂CH₂—O—C₁₀ H ₇); Hz 8.16 (d, 1H, ³J=9.8 Hz, H-4).¹³C-NMR (DMSO-d₆, 75 MHz): δ/ppm (TMS)=25.28 and 26.39(5-O—CH₂(CH₂)₂CH₂—O—C₁₀H₇); 67.37 and 72.20 (5-O—CH₂(CH₂)₂ CH₂—O—C₁₀H₇);93.06 (C-8); 105.07, 119.73, 121.28, 124.86, 125.03, 126.13, 126.29,127.36 and 133.95 (5-O—CH₂(CH₂)₂CH₂—O—C ₁₀H₇); 105.61 (C-4′); 105.87(C-4a); 112.14 (C-3); 112.78 (C-6); 139.34 (C-4); 145.79 (C-5″); 148.61(C-5); 152.06 (C-8a); 157.60 (C-7); 153.88 (C-1″); 160.02 (C-2). IR(KBr): ν/cm⁻¹=2956, 1728, 1624, 1578, 1456, 1344, 1268, 1128. MS (EI):m/z (%)=400 M⁺ (35), 257 (42), 215 (26), 199 [C₁₄H₁₅O]⁺ (100), 157[C₁₁H₉O]⁺ (96), 127 (40), 89 (12), 55 [C₄H₇]⁺ (97).

Example 23 5-(4-[2-Naphthyloxy]butoxy)psoralen (AS120)4-(4-[2-Naphthyloxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 122° C. Combustion analysis: C₂₅H₂₀O₅ (400.44)calculated: C 74.99 H 5.30 found: C 75.28 H 5.22

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=2.04 (s, 4H, 5-O—CH₂(CH₂)₂CH₂—O—C₁₀H₇); 4.21 (s, 2H, 5-O—CH₂(CH₂)₂CH ₂—O—C₁₀H₇); 4.60 (s, 2H,5-O—CH ₂(CH₂ ₂CH₂—O—C₁₀H₇); 6.22 (d, 1H, ³J=9.8 Hz, H-3); 7.14 (dd, 1H,³J=8.9 Hz, ⁵J=2.4 Hz, H-3″); 7.27-7.36 (m, 4H, H-8, H-4′ and5-O—CH₂(CH₂)₂CH₂—O—C₁₀ H ₇); 7.45 (t, 1H, ³J=7.5 Hz,5-O—CH₂(CH₂)₂CH₂—O—C₁₀ H ₇); 7.76-7.83 (m, 3H, 5-O—CH₂(CH₂)₂CH₂—O—C₁₀ H₇); 800 (d, 1H, ³J=2.3 Hz, H-5′); Hz 8.17 (d, 1H, ³J=9.8 Hz, H-4).¹³C-NMR (DMSO-d₆, 75 MHz): δ/ppm (TMS)=25.21 and 26.22(5-O—CH₂(CH₂)₂CH₂—O—C₁₀H₇); 67.16 and 72.26 (5-O—CH₂(CH₂)₂ CH₂—O—C₁₀H₇);93.13 (C-8); 105.65 (C-4′); 105.92 (C-4a); 106.74, 118.64, 123.47,126.32, 126.58, 127.45, 128.41, 129.22 and 134.27 (5-O—CH₂(CH₂)₂CH₂—O—C₁₀H₇); 112.21 (C-3); 112.86 (C-6); 139.38 (C-4); 145.86 (C-5′); 148.71(C-5); 152.11 (C-8a); 156.38 (C-1″); 157.64 (C-7); 160.04 (C-2). IR(KBr): ν/cm⁻¹=1732, 1626, 1600,1460, 1354, 1260. MS (EI): m/z (%)=400 M⁺(20), 257 (5), 215 (5), 199 [C₁₄H₁₅O]⁺ (97), 157 [C₁₁H₉O]⁺ (100), 127(49), 89 (8), 55 [C₄H₇]⁺ (72).

Example 24 5-[3-(4-Methoxyphenoxy)propoxy]psoralen (AS79)4-[3-(4-Methoxyphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 139.5° C. Combustion analysis: C₂₁H₁₈O₆ (366.37)calculated: C 68.85 H 4.95 found: C 68.56 H 5.07

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=2.24 (t, 2H, ³J=6.0 Hz, 5-O—CH₂CH₂CH₂—O—C₆H₄—OCH₃); 3.68 (s, 3H, —OCH ₃); 4.15 (t, 2H, ³J=6.0 Hz,5-O—CH₂CH₂CH ₂—O—C₆H₄—OCH₃); 4.63 (t, 2H, ³J=5.9 Hz, 5-O—CH₂CH₂CH₂—O—C₆H₄—OCH₃); 6.28 (d, 1H, ³J=9.8 Hz, H-3); 6.82-6.90 (m, 4H,5-O—CH₂CH₂CH₂—O—C₆ H ₄—OCH₃); 7.31-7.32 (m, 2H, H-8 and H-4′); 8.02 (s,1H, H-5′); 8.20 (d, 1H, ³J=9.8 Hz, H-4). ¹³C-NMR (DMSO-d₆, 75 MHz):δ/ppm (TMS)=29.30 (5-O—CH₂ CH₂CH₂—O—C₆H₄OCH₃); 55.29 (—OCH₃); 64.55 und69.52 (5-O—CH₂CH₂ CH₂—O—C₆H₄OCH₃); 93.33 (C-8); 105.38 (C-4′); 106.08(C-4a); 112.30 (C-3); 113.02 (C-6); 114.56 and 115.35 (C-2″, C-3″, C-5″and C-6″); 139.42 (C-4); 145.96 (C-5′); 148.54 (C-5); 152.05 (C-8a);152.40 and 153.37 (C-1″ and C-4″); 157.55 (C-7); 160.02 (C-2). IR (KBr):ν/cm⁻¹=3125, 2952, 2828, 1721, 1622, 1508, 1456, 1352, 1233, 1129. MS(EI): m/z (%)=366 M⁺ (32), 243 (18), 215 (17), 202 [C₁₁H₆O₄]⁺ (18), 165[C₁₀H₁₃O₂]⁺ (100), 145 (10), 137 [CH₃—O—C₆H₄O—CH₂]⁺ (94), 109 (30), 92(17), 77 [C₆H₅]⁺ (35), 51 (14), 44 (40).

Example 25 5-[3-(3-Methoxyphenoxy)propoxy]psoralen (AS64)4-[3-(3-Methoxyphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 154.5° C. Combustion analysis: C₂₁H₁₈O₆ (366.37)calculated: C 68.85 H 4.95 found: C 68.57 H 5.05

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=2.27 (quint, 2H, ³J=6.1 Hz,5-O—CH₂CH ₂CH₂—O—C₆H₄—OCH₃); 3.72 (s, 6H, —OCH ₃); 4.22 (t, 2H, ³J=6.2Hz, 5-O—CH₂CH₂CH ₂—O—C₆H₄—OCH₃); 4.66 (t, 2H, ³J=6.0 Hz, 5-O—CH₂CH₂CH₂—O—C₆H₄—OCH₃); 6.30 (d, 1H, ³J=9.8 Hz, H-3); 6.50-6.55 (m, 3H,H-2″, H-4″ and H-6″); 7.17 (t, 1H, ³J=8.5 Hz, H-5″); 7.33 (d, 1H, ³J=2.2Hz, H-4′); 7.36 (s, 1H, H-8); 8.04 (d, 1H, ³J=2.2 Hz, H-5″); 8.24 (d,1H, ³J=9.8 Hz, H-4). ¹³C-NMR (DMSO-d₆, 75 MHz): δ/ppm (TMS)=29.20(5-O—CH₂ CH₂CH₂—O—C₆H₄—OCH₃); 55.01 (—OCH₃); 64.10 and 69.49 (5-O—CH₂CH₂CH₂—O—C₆H₄—OCH₃); 93.35 (C-8); 100.70 (C-5″); 105.41 (C-4′); 106.09(C-4a); 106.30 and 106.61 (C-4″ and C-6″); 112.31 (C-3); 113.01 (C-6);129.91 (C-2″); 139.49 (C-4); 145.99 (C-5′); 148.55 (C-5); 152.06 (C-8a);157.56 (C-7); 159.65 and 160.46 (C-1″ and C-3″); 160.02 (C-2). IR (KBr):ν/cm⁻¹=3125, 2956, 1724, 1618, 1455, 1352, 1270, 1175. MS (EI): m/z(%)=366 M⁺(16), 202 [C₁₁H₆O₄]⁺ (7), 165 [C₁₀H₁₃O₂]⁺ (100), 137[CH₃—O—C₆H₄O—CH₂]⁺ (80), 124 (8), 107 [C₆H₅O—CH₂]⁺ (30), 92 (16), 77[C₆H₅]⁺ (32), 64 (8), 51 (10), 41 [C₃H₅]⁺ (24).

Example 26 5-[3-(3,5-Dimethoxyphenoxy)propoxy]psoralen (AS104)4-[3-(3,5-Dimethoxyphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 154.5° C. Combustion analysis: C₂₂H₂₀O₇ (396.40)calculated: C 66.66 H 5.09 found: C 66.43 H 5.06

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=1.97 (t, 2H, ³J=5.7 Hz, 5-O—CH₂CH₂CH₂—O—C₆H₃—(OCH₃)₂); 3.70 (s, 3H, —(OCH ₃)₂); 4.20 (t, 2H, ³J=5.8 Hz,5-O—CH₂CH₂CH ₂—O—C₆H₃—(OCH₃)₂); 4.65 (t, 2H, ³J=5.6 Hz, 5-O—CH₂CH₂CH₂—O—C₆H₃—(OCH₃)₂); 6.09-6.12 (m, 3H, H-2″, H-4″ and H-6″); 6.29(d, 1H, ³J=9.8 Hz, H-3); 7.33 (s, 2H, H-8 and H-4′); 8.03 (s, 1H, H-5′);8.24 (d, 1H, ³J=9.8 Hz, H-4). ¹³C-NMR (DMSO-d₆, 75 MHz): δ/ppm(TMS)=29.17 (5-O—CH₂ CH₂CH₂—O—C₆H₃—(OCH₃)₂); 55.07 (—(OCH₃)₂); 64.16 and69.44 (5-O—CH₂CH₂ CH₂-—O—C₆H₃-(OCH₃)₂); 92.92 (C-8); 93.29 (C-2″, C-4″and C-6″); 105.40 (C-4′); 106.05 (C-4a); 112.26 (C-3); 112.96 (C-6);139.48 (C-4); 145.95 (C-5′); 148.53 (C-5); 152.05 (C-8a); 157.56 (C-7);160.01 (C-2); 160.27 (C-1″); 161.11 (C-3″ and C-5″). IR (KBr):ν/cm⁻¹=3082, 2939, 1727, 1605, 1456, 1387, 1156. MS (EI): m/z (%)=396 M⁺(12), 202 [C₁₁H₆O₄]⁺ (3), 195 [C₁₁H₁₅O₃]⁺ (100), 167[(CH₃—O)₂—C₆H₃O—CH₂]⁺ (53), 154 (11), 137 [CH₃—O—C₆H₄O—CH₂]⁺ (19), 122(13), 107 [C₆H₅O—CH₂]⁺ (7), 77 [C₆H₅]⁺ (9), 51 (6), 41 [C₃H₅]⁺ (6).

Example 27 5-[3-(4-Nitrophenoxy)propoxy]psoralen (AS92)4-[3-(4-Nitrophenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 179° C. Combustion analysis: C₂₀H₁₅NO₇ (381.35)Calculated: C 62.99 H 3.96 N 3.67 Found:

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=2.32-2.36 (m, 2H, 5-O—CH₂CH₂CH₂—O—C₆H₄—NO₂); 4.40 (t, 2H, ³J=6.1 Hz, 5-O—CH₂CH₂CH ₂—O—C₆H₄—NO₂);4.68 (t, 2H, ³J=5.7 Hz, 5-O—CH ₂CH₂CH₂—O—C₆H₄—NO₂); 6.31 (d, 1H, ³J=9.8Hz, H-3); 7.18 (d, 2H, ³J=9.0 Hz, 5-O—CH₂CH₂CH₂—O—C₆ H ₄-NO₂); 7.34 (s,2H, H-8 and H-4′); 8.04 (s, 1H, H-5′); 8.19-8.27 (m, 3H, H-4 and5-O—CH₂CH₂CH₂—O—C₆ H ₄—NO₂). ¹³C-NMR (DMSO-d₆, 75 MHz): δ/ppm(TMS)=28.93 (5-O—CH₂ CH₂CH₂—O—C₆H₄—NO₂); 65.44 and 69.29 (5-O—CH₂CH₂CH₂—O—C₆H₄—NO₂); 93.36 (C-8); 105.40 (C-4′); 106.05 (C-4a); 112.33(C-3); 112.96 (C-6); 114.99 (C-2″ and C-6″); 125.82 (C-3″ and C-5″);139.48 (C-4); 140.80 (C-4″); 146.00 (C-5′); 148.46 (C-5); 152.04 (C-8a);157.55 (C-7); 160.01 (C-2); 163.72 (C-1″). IR (KBr): ν/cm⁻¹=3153, 2945,2358, 1716, 1520, 1352, 1266, 1132. MS (EI): m/z (%)=381 M⁺ (49), 202[C₁₁H₆O₄]⁺ (100), 174 [202-CO]⁺ (31), 152 [O₂N—C₆H₄O—CH₂]⁺ (52), 119(35), 106 (16), 75 (23), 51 (26), 41 [C₃H₅]⁺ (55).

Example 28 5-[3-(4-Chlorphenoxy)propoxy]psoralen (AS132)4-[3-(4-Chlorphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 137.5° C. Combustion analysis: C₂₀H₁₅ClO₅ (370.79)calculated.: C 64.79 H 4.08 found.: C 64.47 H 4.18

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=2.28 (quint, 2H, ³J=6.1 Hz,5-O—CH₂CH ₂CH₂—O—C₆H₄—Cl); 4.23 (t, 2H, ³J=6.2 Hz, 5-O—CH₂CH₂CH₂—O—C₆H₄—Cl); 4.65 (t, 2H, ³J=6.1 Hz, 5-O—CH ₂CH₂CH₂—O—C₆H₄—Cl); 6.30(d, 1H, ³J=9.8 Hz, H-3); 6.96-7.02 (m, 2H, 5-O—CH₂CH₂CH₂—O—C₆ H ₄—Cl);7.29-7.34 (m, 4H, H-8, H-4′ and 5-O—CH₂CH₂CH₂—O—C₆ H ₄—Cl); 8.03 (d, 1H,³J=2.4 Hz, H-5′); 8.23 (d, 1H, ³J=9.7 Hz, H-4). ¹³C-NMR (DMSO-d₆, 75MHz): δ/ppm (TMS)=29.09 (5-O—CH₂ CH₂CH₂—O—C₆H₄—Cl); 64.54 and 69.40(5-O—CH₂CH₂ CH₂—O—C₆H₄—Cl); 93.33 (C-8); 105.37 (C-4′); 106.05 (C-4a);112.30 (C-3); 112.98 (C-6); 116.17 (C-2″ and C-6″); 124.23 (C-4″);129.16 (C-3″ and C-5″); 139.44 (C-4); 145.96 (C-5′); 148.49 (C-5);152.03 (C-8a); 157.24 (C-7); 157.54 (C-1″); 159.99 (C-2). IR (KBr):ν/cm⁻¹=3129, 2953, 1716, 1621, 1578, 1492, 1353, 1251. MS (EI): m/z(%)=370 M⁺ (38), 202 [C₁₁H₆O₄]⁺ (88), 169 [C₉H₁₀OCl]⁺ (69), 141[Cl—C₆H₄O—CH₂]⁺ (100), 111 (39), 75 (23), 41 [C₃H₅]⁺ (88).

Example 29 5-[3-(4-Phenoxyphenoxy)propoxy]psoralen (AS122)4-[3-(4-Phenoxyphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 133.5° C. Combustion analysis: C₂₆H₂₀O₆ (428.45)calculated: C 72.89 H 4.71 found: C 73.23 H 4.81

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=2.29 (quint, 2H, ³J=6.0 Hz,5-O—CH₂CH ₂CH₂—O—C₆H₄—O—C₆H₅); 4.23 (t, 2H, ³J=6.1 Hz, 5-O—CH₂CH₂—O—C₆H₄—O—C₆H₅); 4.67 (t, 2H, ³J=6.0 Hz, 5-O—CH ₂CH₂CH₂—O—C₆H₄—O—C₆H₅);6.30 (d, 1H, ³J=9.7 Hz, H-3); 6.91 (d, 2H, ³J=8.1 Hz, —O—C₆ H ₄—O—C₆ H₅); 6.96-7.02 (m, 4H, 5-O—CH ₂CH₂CH₂—O—C₆H₄—O—C₆H₅); 7.07 (t, 1H, ³J=7.3Hz, H-4′″); 7.32-7.37 (m, 4H, H-8, H-4′ and —O—C₆ H ₄—O—C₆ H ₅); 8.04(d, 1H, ³J=1.9 Hz, H-5′); 8.24 (d, 1H, ³J=9.8 Hz, H-4). ¹³C-NMR(DMSO-d₆, 75 MHz): δ/ppm (TMS)=29.24 (5O—CH₂ CH₂CH₂—O—C₆H₄—O—C₆H₅);64.52 und 69.47 (5-O—CH₂CH₂ CH₂—O—C₆H₄—O—C₆H₅); 93.33 (C-8); 105.42(C-4′); 106.06 (C-4a); 112.31 (C-3); 112.98 (C-6); 139.47 (C-4); 145.97(C-5′); 148.54 (C-5); 152.06 (C-8a); 157.57 (C-7); 160.02 (C-2); 115.68,117.23, 120.62, 122.52, 129.80, 149.45, 154.76 and 157.91 (—O—C ₆H₄—O—C₆H₅). IR (KBr): ν/cm⁻¹=3124, 2954, 1716, 1578, 1506, 1456, 1348, 1222.MS (EI): m/z (%)=428 M⁺ (50), 227 (19), 199 (57), 171 (6), 134 (100), 77[C₆H₅]⁺ (43), 51 (15).

Example 30 5-[3-(4-Methylphenoxy)propoxy]psoralen (AS127)4-[3-(4-Methylphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 126.5° C. Combustion analysis: C₂₁H₁₈O₅ (350.37)calculated: C 71.99 H 5.18 found: C 72.27 H 5.24

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=2.22-2.30 (m, 5H, 5-O—CH₂CH₂CH₂—O—C₆H₄—CH₃ and —CH₃); 4.18 (t, 2H, ³J=6.2 Hz, 5-O—CH₂CH₂CH₂—O—C₆H₄—CH₃); 4.63 (t, 2H, ³J=6.1 Hz, 5-O—CH ₂CH₂CH₂—O—C₆H₄—CH₃); 6.28(d, 1H, ³J=9.8 Hz, H-3); 6.80 (d, 2H, ³J=8.5 Hz, H-3″ and H-5″); 7.07(d, 2H, ³J=8.3 Hz, H-2″ and H-6″); 7.31 (d, 1H, ³J=2.3 Hz, H-4′); 7.33(s, 1H, H-8); 8.02 (d, 1H, ³J=2.4 Hz, H-5′); 8.15 (d, 1H, ³J=9.8 Hz,H-4). ¹³C-NMR (DMSO-d₆, 75 MHz): δ/ppm (TMS)=20.01 (—CH₃); 29.27(5-O—CH₂ CH₂CH₂—O—C₆H₄—CH₃); 64.06 and 69.54 (5-O—CH₂CH₂CH₂—O—C₆H₄—CH₃); 93.35 (C-8); 105.39 (C-4′); 106.11 (C-4a); 112.33(C-3); 113.04 (C-6); 114.29 (C-3″ and C-5″); 129.20 (C-4″); 129.78 (C-2″and C-6″); 139.45 (C-4); 145.98 (C-5′); 148.55 (C-5); 152.07 (C-8a);156.30 (C-1″); 157.57 (C-7); 160.04 (C-2). IR (KBr): ν/cm⁻¹=3126, 2954,1720, 1622, 1511, 1454, 1351, 1240, 1129. MS (EI): m/z (%)=350 M⁺ (37),215 (5), 202 [C₁₁H₆O₄]⁺ (38), 174 (6), 149 [C₁₀H₁₃O]⁺ (87), 121[CH₃—C₆H₄O—CH₂]⁺ (100), 91 [C₇H₇]⁺ (58), 41 [C₃H₅]⁺ (22).

Example 31 5-[3-(4-Ethylphenoxy)propoxy]psoralen (AS123)4-[3-(4-Ethylphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 122° C. Combustion analysis: C₂₂H₂₀O₅ (364.40)calculated: C 72.51 H 5.53 found: C 72.50 H 5.62

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=1.14 (t, 3H, ³J=7.6 Hz, —CH₂CH₃); 2.27 (quint, ³J=7.6 Hz, 2H, 5-O—CH₂CH ₂CH₂—O—C₆H₄—CH₂CH₃); 2.53 (q,2H, ³J=7.7 Hz, —CH ₂CH₃); 4.20 (t, 2H, ³J=6.2 Hz, 5-O—CH₂CH₂CH₂—O—C₆H₄—CH₂CH₃); 4.56 (t, 2H, ³J=6.0 Hz, 5-O—CH ₂CH₂CH₂—O—C₆H₄—CH₂CH₃);6.30 (d, 1H, ³J=9.8 Hz, H-3); 6.87 (d, 2H, ³J=8.4 Hz, H-3″ and H-5″);7.10 (d, 2H, ³J=8.4 Hz, H-2″ and H-6″); 7.33 (d, 1H, ³J=1.4 Hz, H-4′);7.35 (s, 1H, H-8); 8.04 (d, 1H, ³J=2.2 Hz, H-5′); 8.23 (d, 1H, ³J=9.8Hz, H-4). ¹³C-NMR (DMSO-d₆, 75 MHz): δ/ppm (TMS)=15.80 (—CH₃); 27.17(—CH₂CH₃); 29.21 (5-O—CH₂CH₂CH₂—O—C₆H₄—C₂H₅); 64.00 and 69.49(5-O—CH₂CH₂ CH₂—O—C₆H₄—C₂H₅); 93.31 (C-8); 105.36 (C-4′); 106.06 (C-4a);112.28 (C-3); 112.98 (C-6); 114.26 (C-3″ and C-5″); 128.53 (C-2″ andC-6″); 135.73 (C-4″); 139.42 (C-4); 145.94 (C-5′); 148.51 (C-5); 152.02(C-8a); 156.41 (C-1″); 157.52 (C-7); 159.98 (C-2). IR (KBr):ν/cm⁻¹=3124, 2952, 1724, 1622, 1512, 1454, 1350, 1238. MS (EI): m/z(%)=364 M⁺ (28), 243 (3), 202 [C ₁₁H₆O₄]⁺ (32), 163 [C₁₁H₁₅O]⁺ (68), 135[CH₃—CH₂C₆H₄O—CH₂]⁺ (100), 107 [C₈H₁₁]⁺ (43), 79 (34), 41 [C₃H₅]⁺ (19).

Example 32 5-[3-(4—Fluorphenoxy)propoxy]psoralen (AS133)4-[3-(4—Fluorphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 123° C. Combustion analysis: C₂₀H₁₅FO₅ (354.34)calculated: C 67.79 H 4.27 found: C 68.04 H 4.42

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=2.28 (quint, 2H, ³J=6.1 Hz,5-O—CH₂CH ₂CH₂—O—C₆H₄—F); 4.21 (t, 2H, ³J=6.2 Hz, 5-O—CH₂CH₂—O—C₆H₄—F);4.65 (t, 2H, ³J=6.0 Hz, 5-O—CH ₂CH₂CH₂—O—C₆H₄—F); 6.30 (d, 1H, ³J=9.8Hz, H-3); 6.95-7.00 (m, 2H, 5-O—CH₂CH₂CH₂—O—C₆ H ₄—F); 7.07-7.14 (m, 2H,5-O—CH₂CH₂CH₂—O—C₆ H ₄—F); 7.33 (d, 1H, ³J=2.1 Hz, H-4′); 7.35 (s, 1H,H-8); 8.04 (d, 1H, ³J=2.3 Hz, H-5′); 8.23 (d, 1H, ³J=9.8 Hz, H-4).¹³C-NMR (DMSO-d₆, 75 MHz): δ/ppm (TMS)=29.18 (5O—CH₂ CH₂CH₂—O—C₆H₄—F);64.71 and 69.45 (5O—CH₂CH₂ CH₂—O—C₆H₄—F); 93.34 (C-8); 105.38 (C-4′);106.07 (C-4a); 112.31 (C-3); 113.00 (C-6); 115.60, 115.72 and 115.90(C-2″, C-3″, C-5″ and C-6″); 139.45 (C-4); 145.97 (C-5′); 148.51 (C-5);152.04 (C-8a); 154.72 (C4″); 157.55 (C-7); 158.01 (C-1″); 160.01 (C-2).IR (KBr): ν/cm⁻¹=3128, 2954, 1717, 1620, 1508, 1455, 1353, 1213. MS(EI): m/z (%)=354 M⁺ (26), 202 [C₁₁H₆O₄]⁺ (46), 153 [C₁₀H₁₂OF]⁺ (48),125 [F—C₆H₄O—CH₂]⁺ (100), 95 (36), 83 (13), 41 [C₃H₅]⁺ (64).

Example 33 5-[3-(3-Trifluormethylphenoxy)propoxy]psoralen (AS124)4-[3-(3-Trifluormethylphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 137° C. Combustion analysis: C₂₁H₁₅F₃O₅ (404.35)calculated: C 62.38 H 3.47 found: C 62.13 H 3.78

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=2.30 (t, 2H, ³J=5.5 Hz, 5-O—CH₂CH₂CH₂—O—C₆H₄—CF₃); 4.32 (s, 2H, 5-O—CH₂CH₂CH ₂—O—C₆H₄—CF₃); 4.67 (s, 2H,5-O—CH ₂CH₂CH₂—O—C₆H₄—CF₃); 6.27 (d, 1H, ³J=9.6 Hz, H-3); 7.23-7.33 (m,5H, H-2″, H-4″, H-6″, H-8 and H-4′); 7.51 (t, 1H, ³J=7.7 Hz, H-5″); 8.03(s, 1H, H-5′); 8.23 (d, 1H, ³J=10.0 Hz, H-4). ¹³C-NMR (DMSO-d₆, 75 MHz):δ/ppm (TMS)=29.08 (5-O—CH₂ CH₂CH₂—O—C₆H₄—CF₃); 64.75 and 69.36(5-O—CH₂CH₂₂ CH₂—O—C₆H₄—CF₃); 93.31 (C-8); 105.44 (C-4′); 106.02 (C-4a);110.93, 110.98, 117.06, 117.06, 130.48 and 130.67 (5-O—CH₂(CH₂)₂CH₂—O—C₆H₄—CF₃); 112.26 (C-3); 112.94 (C-6); 118.73 (—CF₃); 139.51 (C-4);145.97 (C-5′); 148.53 (C-5); 152.06 (C-8a); 157.58 (C-7); 158.72 (C-1″);160.01 (C-2). IR (KBr): ν/cm⁻¹=3126, 2924, 1724, 1622, 1454, 1342, 1242,1130. MS (EI): m/z (%)=404 M⁺ (56), 216 (2), 175 [C₁₂H₁₅O]⁺ (100), 145(56), 127 (12), 89 (14), 41 [C₃H₅]⁺ (84).

Example 34 5-[3-(1-Naphthyloxy)propoxy]psoralen (AS135)4-[3-(1-Naphthyloxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 140° C. Combustion analysis: C₂₄H₁₈O₅ (386.41)calculated: C 74.60 H 4.70 found: C 75.33 H 4.81

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=2.43 (quint, 2H, ³J=6.1 Hz,5-O—CH₂CH ₂CH₂—O—C₁₀H₇); 4.43 (t, 2H, ³J=6.0 Hz, 5-O—CH₂CH₂CH₂—O—C₁₀H₇); 4.79 (t, 2H, ³J=6.0 Hz, 5-O—CH ₂CH₂CH₂—O—C₁₀H₇); 6.21 (d,1H, ³J=9.8 Hz, H-3); 7.03 (d, 1H, ³J=7.3 Hz, H-2″); 7.34 (s, 1H, H-8);7.36 (d, 1H, ³J=2.2 Hz, H-4′); 7.39-7.53 (m, 4H, 5-O—CH₂CH₂CH₂—O—C₁₀ H₇); 7.86 (d, 1H, ³J=7.9 Hz, H-5″); 8.03 (d, 1H, ³J=2.3 Hz, H-5′); 8.14(d, 1H, ³J=8.1 Hz, H-8″); 8.24 (d, 1H, ³J=9.8 Hz, H-4). ¹³C-NMR(DMSO-d₆, 75 MHz): δ/ppm (TMS)=29.25 (5-O—CH₂ CH₂CH₂—O—C₁₀H₇); 64.45 and69.66 (5-O—CH₂CH₂ CH₂—O—C₁₀H₇); 93.32 (C-8); 105.07 (C-2″); 105.39(C-4′); 106.06 (C-4a); 112.20 (C-3); 113.01 (C-6); 119.73 (C-4″); 121.28(C-8″); 124.86, 125.03, 126.13, 126.29 and 127.36 (C-3″, C-5″, C-6″,C-7″ and C-8a″); 133.95 (C-4a″); 139.39 (C-4); 145.94 (C-5″); 148.55(C-5); 152.03 (C-8a); 153.84 (C-1″); 157.54 (C-7); 159.97 (C-2). IR(KBr): ν/cm⁻¹=3126, 2949, 1721, 1622, 1580, 1454, 1351, 1129. MS (EI):m/z (%)=386 M⁺ (63), 243 (25), 215 (24), 185 [C₁₃H₁₃O]⁺ (100), 157[C₁₁H₉O]⁺ (65), 115 (36), 89 (12), 41 [C₃H₅]⁺ (13).

Example 35 5-[3-(2-Naphthyloxy)propoxy]psoralen (AS137)4-[3-(2-Naphthyloxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 151° C. Combustion analysis: C₂₅H₂₀O₅ (400.44)calculated: C 74.60 H 4.70 found: C 75.11 H 4.81

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=2.35 (quint, 2H, ³J=6.1 Hz,5-O—CH₂CH ₂CH₂—O—C₁₀H₇); 4.35 (t, 2H, ³J=6.2 Hz, 5-O—CH₂CH₂CH₂—O—C₁₀H₇); 4.68 (t, 2H, ³J=6.0 Hz, 5-O—CH ₂CH₂CH₂—O—C₁₀H₇); 6.25 (d,1H, ³J=9.8 Hz, H-3); 7.17 (dd, 1H, ³J=9.0 Hz, ⁴J=2.4 Hz, H-3″);7.30-7.35 (m, 4H, H-8, H-4′ and 5-O—CH₂CH₂CH₂—O—C₁₀ H ₇); 7.44 (t, 1H,³J=7.0 Hz, H-7″); 7.76-7.82 (m, 3H, 5-O—CH₂CH₂CH₂—O—C₁₀ H ₇); 8.01 (d,1H, ³J=2.2 Hz, H-5′); 8.22 (d, 1H, ³J=9.8 Hz, H-4). ¹³C-NMR (DMSO-d₆, 75MHz): δ/ppm (TMS)=29.22 (5-O—CH₂ CH₂CH₂—O—C₁₀H₇); 64.26 and 69.52(5-O—CH₂CH₂ CH₂—O—C₁₀H₇); 93.31 (C-8); 105.42 (C-4′); 106.05 (C-4a);106.80 (C-1″); 112.28 (C-3); 112.96 (C-6); 118.60 (C-3″); 123.53 (C-6″);126.33, 126.60, 127.44, 128.46 and 129.27 (C-4″, C-4a″, C-5″, C-7″ andC-8″); 134.23 (C-8a″); 139.45 (C-4); 145.96 (C-5′); 148.52 (C-5); 152.06(C-8a); 156.32 (C-2″); 157.57 (C-7); 160.02 (C-2). IR (KBr):ν/cm⁻¹=3133, 3046, 1720, 1452, 1349, 1130. MS (EI): m/z (%)=386 M⁺ (59),215 (6), 185 [C₁₃H₁₃O]⁺ (100), 157 [C₁₁H₉O]⁺ (59), 127 (41), 89 (8), 41[C₃H₅]⁺ (8).

Example 36 5-(5-Phenoxypentoxy)psoralen (AS121)4-(5-Phenoxypentoxy)-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 91° C. Combustion analysis: C₂₂H₂₀O₅ (364.40) calculated:C 72.51 H 5.53 found: C 72.74 H 5.68

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=1.63-1.71 (m, 2H, 5-O—CH₂CH₂CH₂CH₂CH₂—O—C₆H₅); 1.77-1.93 (m, 4H, 5-O—CH₂CH ₂CH₂CH ₂CH₂—O—C₆H₅); 4.00(t, 2H, ³J=6.2 Hz, 5-O—CH₂CH₂CH₂CH₂CH ₂—O—C₆H₅); 4.52 (t, 2H, ³J=6.0 Hz,5-O—CH ₂CH₂CH₂CH₂CH₂—O—C₆H₅); 6.30 (d, 1H, ³J=9.7 Hz, H-3); 6.90-6.93(m, 3H, 5-O—CH₂CH₂CH₂CH₂CH₂—O—C₆ H ₅); 7.25-7.33 (m, 4H, H-8, H-4′ and5O—CH₂CH₂CH₂CH₂CH₂—O—C₆ H ₅); 8.02 (s, 1H, H-5′); 8.19 (d, 1H, ³J=9.7Hz, H-4). ¹³C-NMR (DMSO-d₆, 75 MHz): δ/ppm (TMS)=22.02 (5-O—CH₂CH₂CH₂CH₂CH₂-—O—C₆H₅); 28.31 and 29.01 (5-O—CH₂ CH₂CH₂ CH₂CH₂—O—C₆H₅);67.06 and 74.29 (5-O—CH₂CH₂CH₂CH₂ CH₂—O—C₆H₅); 93.20 (C-8); 105.55(C-4′); 106.04 (C-4a); 112.30 (C-3); 113.01 (C-6); 114.34 (C-3″ andC-5″); 120.32 (C-4″); 129.39 (C-2″ and C-6″); 139.38 (C-4); 145.88(C-5′); 148.74 (C-5); 152.08 (C-8a); 157.59 (C-1″); 158.58 (C-7); 160.05(C-2). IR (KBr): ν/cm⁻¹=3130, 2946, 2872, 1716, 1602, 1496, 1350, 1242,1134. MS (EI): m/z (%)=364 M⁺ (9), 202 [C₁₁H₆O₄]⁺ (22), 163 [C₁₁H₁₅O]⁺(44), 107 [C₆H₅O—CH₂]⁺ (40), 69 [C₅H₉]⁺ (100), 41 [C₃H₅]⁺ (52).

Example 37 5-[5-(4-Methoxyphenoxy)pentoxy]psoralen (AS125)4-[5-(4-Methoxyphenoxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 87.5° C. Combustion analysis: C₂₃H₂₂O₆ (394.43)calculated: C 70.04 H 5.62 found: C 69.32 H 5.63

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=1.61-1.93 (m, 6H, 5-O—CH₂CH ₂CH₂CH ₂CH₂—O—C₆H₄—OCH₃); 3.68 (s, 3H, —OCH ₃); 3.93 (t, 2H, ³J=6.1 Hz,5-O—CH₂CH₂CH₂CH₂CH ₂—O—C₆H₄—OCH₃); 4.52 (t, 2H, ³J=6.2 Hz, 5-O—CH₂CH₂CH₂CH₂CH₂—O—C₆H₄—OCH₃); 6.31 (d, 1H, ³J=9.8 Hz, H-3); 6.84 (s, 4H,5-O—CH₂CH₂CH₂CH₂CH₂—O—C₆ H ₄—OCH₃); 7.32 (d, 1H, ³J=2.3 Hz, H-4′); 7.35(s, 1H, H-8); 8.03 (d, 1H, ³J=2.4 Hz, H-5′); 8.20 (d, 1H, ³J=9.8 Hz,H-4). ¹³C-NMR (DMSO-d₆, 75 MHz): δ/ppm (TMS)=22.03 (5-O—CH₂CH₂CH₂CH₂CH₂—O—C₆H₄—OCH₃); 28.39 und 29.03 (5-O—CH₂ CH₂CH₂CH₂CH₂—O—C₆H₄—OCH₃); 55.31 (—OCH₃); 64.55 and 69.52 (5-O—CH₂CH₂CH₂CH₂CH₂—C₆H₄—OCH₃); 93.24 (C-8); 105.57 (C-4′); 106.08 (C-4a); 112.34 (C-3);113.05 (C-6); 114.54 and 115.26 (C-2″, C-3″, C-5″ and C-6″); 139.42(C-4); 145.91 (C-5′); 148.77 (C-5); 152.10 (C-8a); 152.61 and 153.22(C-1″ and C-4″); 157.61 (C-7); 160.08 (C-2). IR (KBr): ν/cm⁻¹=3123,2932, 2866, 1725, 1628, 1508, 1457, 1343, 1232, 1130.

Example 38 5-[5-(3,5-Dimethoxyphenoxy)pentoxy]psoralen (AS126)4-[5-(3,5-Dimethoxyphenoxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 134.5° C. Combustion analysis: C₂₄H₂₄O₇ (424.45)calculated: C 67.92 H 5.66 found: C 68.30 H 5.85

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=1.64-1.86 (m, 6H, 5-O—CH₂CH ₂CH₂CH ₂CH₂—O—C₆H₃—(OCH₃)₂); 3.69 (s, 6H, —(OCH ₃)₂); 3.96 (s, 2H,5-O—CH₂CH₂CH₂CH₂CH ₂—O—C₆H₃—(OCH₃)₂); 4.51 (t, 2H, 5-O—CH₂CH₂CH₂CH₂CH₂—O—C₆H₃—(OCH₃)₂); 6.07 (s, 3H, H-2″, H-4″ and H-6″); 6.30(d, 1H, ³J=9.3 Hz, H-3); 7.33 (s, 2H, H-8 and H-4′); 8.02 (s, 1H, H-5′);8.19 (d, 1H, ³J=9.2 Hz, H-4). ¹³C-NMR (DMSO-d₆, 75 MHz): δ/ppm(TMS)=22.01 (5-O—CH₂CH₂ CH₂CH₂CH₂—O—C₆H₃—(OCH₃)₂); 28.26 and 29.00(5-O—CH₂ CH₂CH₂ CH₂CH₂—O—C₆H₃—(OCH₃)₂); 55.06 (—(OCH₃)₂); 67.24 and72.48 (5-O—CH₂CH₂CH₂CH₂ CH₂—O—C₆H₃—(OCH₃)₂); 92.76 (C-8); 93.20 (C-2″,C-4″ and C-6″); 105.56 (C-4′); 106.04 (C-4a); 112.30 (C-3); 113.01(C-6); 139.39 (C-4); 145.88 (C-5′); 148.75 (C-5); 152.09 (C-8a); 157.60(C-7); 160.05 (C-2); 160.48 (C-1″); 161.10 (C-3″ and C-5″). IR (KBr):ν/cm⁻¹=3120, 2956, 1720, 1602, 1456, 1354, 1208. MS (EI): m/z (%)=424M⁺(27), 270 (6), 223 [C₁₃H₁₉O₃]⁺ (100), 202 [C₁₁H₆O₄]⁺ (19), 155 (81),137 [CH₃—O—C₆H₄O—CH₂]⁺ (28), 69 (82), 41 [C₃H₅]⁺ (70).

Example 39 5-[5-(4-Nitrophenoxy)pentoxy]psoralen (AS139)4-[5-(4-Nitrophenoxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 126.5° C. Combustion analysis: C₂₂H₁₉NO₇ (409.40)calculated: C 64.54 H 4.86 N 3.42

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=1.52-1.57 (m, 2H, 5-O—CH₂CH₂CH₂CH₂CH₂—O—C₆H₄—NO₂); 1.66-1.68 (m, 4H, 5-O—CH₂CH ₂CH₂CH₂CH₂—O—C₆H₄—NO₂); 4.17 (s, 2H, 5-O—CH₂CH₂CH₂CH₂CH ₂—O—C₆H₄—NO₂); 4.52(s, 2H, 5-O—CH ₂CH₂CH₂CH₂CH₂—O—C₆H₄—NO₂); 6.32 (d, 1H, ³J=9.9 Hz, H-3);7.14 (d, 2H, ³J=7.7 Hz, 5-O—CH₂CH₂CH₂CH₂CH₂—O—C₆ H ₄—NO₂); 7.32 (s, 2H,H-8 and H-4′); 8.02 (s, 1H, H-5′); 8.17-8.20 (m, 3H, H-4 and5-O—CH₂CH₂CH₂CH₂CH₂—O—C₆ H ₄—NO₂). ¹³C-NMR (CDCl₃, 75 MHz): δ/ppm(TMS)=22.66 (5-O—CH₂CH₂ CH₂CH₂CH₂—O—C₆H₄—NO₂); 28.78 and 29.76 (5-O—CH₂CH₂CH₂ CH₂CH₂—O—C₆H₄—NO₂); 68.47 and 72.66 (5-O—CH₂CH₂CH₂CH₂CH₂—O—C₆H₄—NO₂); 94.02 (C-8); 105.06 (C-4′); 106.8 (C-4a); 112.68 (C-3);113.35 (C-6); 114.39 (C-2″ and C-6″); 125.95 (C-3″ and C-5″); 139.18(C-4); 141.54 (C-4″); 144.89 (C-5′); 148.91 (C-5); 152.75 (C-8a); 158.29(C-7); 161.13 (C-2); 164.00 (C-1″). IR (KBr): ν/cm⁻¹=3126, 2959, 1729,1594, 1507, 1339, 1264. MS (EI): m/z (%)=409 M⁺ (19), 202 [C₁₁H₆O₄]⁺(58), 174 [202-CO]⁺ (21), 152 [O₂N—C₆H₄O—CH₂]⁺ (17), 69 (100), 41[C₃H₅]⁺ (79).

Example 40 5-[5-(4-Chlorphenoxy)pentoxy]psoralen (AS131)4-[5-(4-Chlorphenoxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 126.5° C. Combustion analysis: C₂₂H₁₉ClO₅ (398.85)calculated: C 66.25 H 4.80 found: C 66.62 H 4.91

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=1.58-1.68 (m, 2H, 5-O—CH₂CH₂CH₂CH₂CH₂—O—C₆H₄—Cl); 1.75-1.92 (m, 4H, 5-O—CH₂CH ₂CH₂CH ₂CH₂—O—C₆H₄—Cl);3.99 (t, 2H, ³J=6.3 Hz, 5-O—CH₂CH₂CH₂CH₂CH ₂—O—C₆H₄—Cl); 4.50 (t, 2H,³J=6.2 Hz, 5-O—CH ₂CH₂CH₂CH₂CH₂—O—C₆H₄—Cl); 6.30 (d, 1H, ³J=9.8 Hz,H-3); 6.92-6.95 (m, 2H, 5-O—CH₂CH₂CH₂CH₂CH₂—O—C₆ H ₄—Cl); 7.28-7.32 (m,4H, H-8, H-4′ and 5O—CH₂CH₂CH₂CH₂CH₂—O—C₆ H ₄—Cl); 8.01 (d, 1H, ³J=2.3Hz, H-5′); 8.17 (d, 1H, ³J=9.8 Hz, H-4). ¹³C-NMR (DMSO-d6, 75 MHz):δ/ppm (TMS)=21.93 (5-O—CH₂CH₂ CH₂CH₂CH₂—O—C₆H₄—Cl); 28.17 and 28.96(5-O—CH₂ CH₂CH₂ CH₂CH₂—O—C₆H₄—Cl) 67.59 and 72.43 (5-O—CH₂CH₂CH₂CH₂CH₂—O—C₆H₄—Cl); 93.16 (C-8); 105.53 (C-4′); 106.00 (C-4a); 112.27 (C-3);112.97 (C-6); 116.09 (C-2″ and C-6″); 123.99 (C-4″); 129.11 (C-3″ andC-5″); 139.34 (C-4); 145.84 (C-5′); 148.70 (C-5); 152.06 (C-8a); 157.42(C-7); 157.57 (C-1″); 160.03 (C-2). IR (KBr): ν/cm⁻¹=3155, 2940, 1719,1622, 1579, 1451, 1350, 1246. MS (EI): m/z (%)=398 M⁺ (10), 197[C₁₁H₁₄OCl]⁺ (30), 174 (11), 141 [Cl—C₆H₄O—CH₂]⁺ (22), 111 (10), 69[C₅H₉]⁺ (100), 41 [C₃H₅]⁺ (50).

Example 41 5-[5-(4-Phenoxyphenoxy)pentoxy]psoralen (AS138)4-[5-(4-Phenoxyphenoxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 100° C. Combustion analysis: C₂₈H₂₄O₆ (456.50)calculated: C 73.67 H 5.30 found: C 73.49 H 5.36

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=1.61-1.68 (m, 2H, 5-O—CH₂CH₂CH₂CH₂CH₂—O—C₆H₄—O—C₆H₅); 1.77-1.94 (m, 4H, 5-O—CH₂CH ₂CH₂CH₂CH₂—O—C₆H₄—O—C₆H₅); 4.00 (t, 2H, ³J=6.2 Hz, 5-O—CH₂CH₂CH₂CH₂CH₂—O—C₆H₄—O—C₆H₅); 4.52 (t, 2H, ³J=6.2 Hz, 5-O—CH₂CH₂CH₂CH₂CH₂—O—C₆H₄—O—C₆H₅); 6.31 (d, 1H, ³J=9.8 Hz, H-3); 6.91-7.00(m, 6H, —O—C₆ H ₄—O—C₆ H ₅); 7.07 (t, 1H, ³J=7.4 Hz, H-4′″); 7.31-7.37(m, 4H, H-8, H-4′ and —O—C₆ H ₄—O—C₆ H ₅); 8.02 (d, 1H, ³J=2.2 Hz,H-5′); 8.18 (d, 1H, ³J=9.8 Hz, H-4). ¹³C-NMR (DMSO-d₆, 75 MHz): δ/ppm(TMS)=22.01 (5-O—CH₂CH₂ CH₂CH₂CH₂—O—C₆H₄—O—C₆H₅); 28.34 and 29.01(5-O—CH₂ CH₂CH₂ CH₂CH₂—O—C₆H₄—O—C₆H₅); 67.63 and 72.46 (5-O—CH₂CH₂CH₂CH₂CH₂—O—C₆H₄—O—C₆H₅); 93.16 (C-8); 105.54 (C-4′); 106.01 (C-4a); 112.27(C-3); 112.97 (C-6); 139.33 (C-4); 145.84 (C-5′); 148.71 (C-5); 152.07(C-8a); 157.58 (C-7); 160.04 (C-2); 115.57, 117.23, 120.58, 122.48,129.79, 149.28, 154.97 and 157.95 (—O—C ₆H₄—O—C ₆H₅). IR (KBr):ν/cm⁻¹=2949, 1725, 1626, 1580, 1340, 1223. MS (EI): m/z (%)=456 M⁺ (39),255 (28), 199 (27), 186 (32), 141 (13), 69 [C₅H₉]⁺ (100), 41 [C₃H₅]⁺(65).

Example 42 5-[5-(4-Methylphenoxy)pentoxy]psoralen (AS129)4-[5-(4-Methylphenoxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 83° C. Combustion analysis: C₂₃H₂₂O₅ (378.43) calculated:C 73.01 H 5.86 found: C 73.41 H 6.09

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=1.64-1.69 (m, 2H, 5-O—CH₂CH₂CH₂CH₂CH₂—O—C₆H₄—CH₃); 1.75-1.90 (m, 4H, 5-O—CH₂CH ₂CH₂CH₂CH₂—O—C₆H₄—CH₃); 2.51 (s, 3H, —CH₃); 3.95 (t, 2H, ³J=6.2 Hz,5-O—CH₂CH₂CH₂CH₂CH ₂—O—C₆H₄—CH₃); 4.51 (t, 2H, ³J=6.1 Hz, 5-O—CH₂CH₂CH₂CH₂CH₂—O—C₆H₄—CH₃); 6.30 (d, 1H, ³J=9.8 Hz, H-3); 6.80 (d, 2H,³J=8.4 Hz, H-3″ and H-5″); 7.06 (d, 2H, ³J=8.2 Hz, H-2″ and H-6″); 7.31(d, 1H, ³J=1.6 Hz, H-4′); 7.33 (s, 1H, H-8); 8.02 (d, 1H, ³J=2.2 Hz,H-5′); 8.18 (d, 1H, ³J=9.8 Hz, H-4). ¹³C-NMR (DMSO-d₆, 75 MHz): δ/ppm(TMS)=19.98 (—CH₃); 22.00 (5-O—CH₂CH₂ CH₂CH₂CH₂—O—C₆H₄—CH₃); 28.32 and29.00 (5-O—CH₂ CH₂CH₂ C ₂CH₂—O—C₆H₄—CH₃); 67.12 and 72.47(5-O—CH₂CH₂CH₂CH₂ CH₂—O—C₆H₄—CH₃); 93.17 (C-8); 105.54 (C-4′); 106.02(C-4a); 112.28 (C-3); 112.99 (C-6); 114.18 (C-3″ and C-5″); 128.90(C-4″); 129.69 (C-2″ and C-6″); 139.36 (C-4); 145.85 (C-5′); 148.72(C-5); 152.07 (C-8a); 156.45 (C-1″); 157.58 (C-7); 160.03 (C-2). IR(KBr): ν/cm⁻¹=3154, 2939, 1722, 1625, 1511, 1457, 1345, 1243, 1131. MS(EI): m/z (%)=378 M⁺ (12), 202 [C₁₁H₆O₄]⁺ (14), 177 [C₁₂H₁₇O]⁺ (53), 121[CH₃—C₆H₄O—CH₂]⁺ (49), 69 [C₅H₉]⁺ (100), 41 [C₃H₅]⁺ (45).

Example 43 5-[5-(4-Ethylphenoxy)pentoxy]psoralen (AS93)4-[5-(4-Ethylphenoxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 88° C. Combustion analysis: C₂₄H₂₄O₅ (392.46) calculated:C 73.45 H 6.16 found: C 73.36 H 6.28

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=1.14 (t, 3H, ³J=7.6 Hz, —CH₂CH₃); 1.61-1.69 (m, 2H, 5-O—CH₂CH₂CH ₂CH₂CH₂—O—C₆H₄—CH₂CH₃); 1.75-1.93 (m,4H, 5-O—CH₂CH ₂CH₂CH ₂CH₂—O—C₆H₄—CH₂CH₃); 2.54 (q, 2H, ³J=7.5 Hz, —CH₂CH₃); 3.96 (t, 2H, ³J=6.3 Hz, 5-O—CH₂CH₂CH₂CH₂CH ₂—O—C₆H₄—CH₂CH₃); 4.52(t, 2H, ³J=6.2 Hz, 5-O—CH₂CH₂CH₂CH₂CH ₂—O—C₆H₄—CH₂CH₃); 6.30 (d, 1H,³J=9.8 Hz, H-3); 6.82 (d, 2H, ³J=8.6 Hz, H-3″ and H-5″); 7.10 (d, 2H,³J=8.5 Hz, H-2″ and H-6″); 7.32 (d, 1H, ³J=1.5 Hz, H-4′); 7.34 (s, 1H,H-8); 8.01 (d, 1H, ³J=2.3 Hz, H-5′); 8.20 (d, 1H, ³J=9.8 Hz, H-4).¹³C-NMR (DMSO-d₆, 75 MHz): δ/ppm (TMS)=15.82 (—CH₃); 22.01 (5-O—CH₂CH₂CH₂CH₂CH₂—O—C₆H₄—C₂H₅); 27.21 (—CH₂CH₃); 28.33 and 29.00 (5-O—CH₂ CH₂CH₂CH₂CH₂—O—C₆H₄—C₂H₅); 67.12 and 72.46 (5-O—CH₂CH₂CH₂CH₂ CH₂—O—C₆H₄—C₂H₅);93.15 (C-8); 105.53 (C-4′); 106.00 (C-4a); 112.26 (C-3); 112.97 (C-6);114.19 (C-3″ and C-5″); 128.50 (C-2″ and C-6″); 135.49 (C-4″); 139.34(C-4); 145.84 (C-5′); 148.71 (C-5); 152.07 (C-8a); 156.63 (C-1″); 157.58(C-7); 160.03 (C-2). IR (KBr): ν/cm⁻¹=3150, 2933, 2866, 1721, 1626,1511, 1458, 1344, 1241. MS (EI): m/z (%)=392 M⁺ (13), 191 [C₁₃H₁₉O]⁺(52), 135 [CH₃—CH₂C₆H₄O—CH₂]⁺ (45), 107 [C₈H₁₁]⁺ (24), 69 [C₅H₉]⁺ (100),41 [C₃H₅]⁺ (48).

Example 44 5-[5-(4—Fluorphenoxy)pentoxy]psoralen (AS128)4-[5-(4—Fluorphenoxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 109° C. Combustion analysis: C₂₂H₁₉FO₅ (382.39)calculated: C 69.10 H 5.01 found: C 69.47 H 5.14

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=1.60-1.66 (m, 2H, 5-O—CH₂CH₂CH₂CH₂CH₂—O—C₆H₄—F); 1.76-1.91 (m, 4H, 5-O—CH₂CH ₂CH₂CH ₂CH₂—O—C₆H₄—F);3.96 (t, 2H, ³J=6.2 Hz, 5-O—CH₂CH₂CH₂CH₂CH ₂—O—C₆H₄—F); 4.50 (t, 2H,³J=6.2 Hz, 5-O—CH ₂CH₂CH₂CH₂CH₂—O—C₆H₄—F); 6.29 (d, 1H, ³J=9.8 Hz, H-3);6.89-6.95 (m, 2H, 5-O—CH₂CH₂CH₂CH₂CH₂—O—C₆ H ₄—F); 7.04-7.12 (m, 2H,5-O—CH₂CH₂CH₂CH₂CH₂—O—C₆ H ₄—F); 7.29 (d, 1H, ³J=2.3 Hz, H-4′); 7.31 (s,1H, H-8); 8.01 (d, 1H, ³J=2.3 Hz, H-5′); 8.17 (d, 1H, ³J=9.8 Hz, H-4).¹³C-NMR (DMSO-d₆, 75 MHz): δ/ppm (TMS)=21.97 (5-O—CH₂CH₂CH₂CH₂CH₂—O—C₆H₄—F); 28.27 and 28.99 (5-O—CH₂ CH₂CH₂ CH₂CH₂—O—C₆H₄—F);67.78 and 72.44 (5-O—CH₂CH₂CH₂CH₂ CH₂—O—C₆H₄—F); 93.15 (C-8); 105.53(C-4′); 105.99 (C-4a); 112.27 (C-3); 112.96 (C-6); 115.49, 115.52,115.59 and 115.83 (C-2″, C-3″, C-5″ and C-6″); 139.33 (C-4); 145.84(C-5′); 148.70 (C-5); 152.06 (C-8a); 154.77 (C-4″); 157.58 (C-7); 157.89(C-1″); 160.03 (C-2). IR (KBr): ν/cm⁻¹=3136, 2944, 2872, 1720, 1626,1504, 1452, 1351, 1134. MS (EI): m/z (%)=382 M⁺ (8), 202 [C₁₁H₆O₄]⁺(21), 181 [C₁₂H₁₆OF]⁺ (37), 125 [F—C₆H₄O—CH₂]⁺ (30), 69 [C₅H₉]⁺ (100),41 [C₃H₅]⁺ (42).

Example 45 5-[5-(1-Naphthyloxy)pentoxy]psoralen (AS136)4-[5-(1-Naphthyloxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 103° C. Combustion analysis: C₂₆H₂₂O₅ (414.46)calculated: C 75.35 H 5.35 found: C 75.56 H 5.43

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=1.71-1.81 (m, 2H, 5-O—CH₂CH₂CH₂CH₂CH₂—O—C₁₀H₇); 1.89-2.00 (m, 1H, 5-O—CH₂CH ₂CH₂CH ₂CH₂—O—C₁₀H₇); 4.18(t, 2H, ³J=6.1 Hz, 5-O—CH₂CH₂CH₂CH₂CH ₂—O—C₁₀H₇) 4.54 (t, 2H, ³J=6.0 Hz,5-O—CH ₂CH₂CH₂CH₂CH₂—O—C₁₀H₇); 6.21 (d, 1H, ³J=9.8 Hz, H-3); 6.94 (d,1H, ³J=7.2 Hz, H-2″); 7.30 (s, 2H, H-8 and H-4′); 7.36-7.53 (m, 4H,5-O—CH₂CH₂CH₂CH₂CH₂—O—C₁₀ H ₇); 7.84 (d, 1H, ³J=7.7 Hz, H-5″); 8.00 (d,1H, ³J=2.2 Hz, H-5′); 8.14 (d, 1H, ³J=8.0 Hz, H-8″); 8.16 (d, 1H, ³J=9.8Hz, H-4). ¹³C-NMR (DMSO-d₆, 75 MHz): δ/ppm (TMS)=22.23 (5-O—CH₂CH₂CH₂CH₂CH₂—O—C₁₀H₇); 28.33 and 29.05 (5-O—CH₂ CH₂CH₂ CH₂CH₂—O—C₁₀H₇);67.48 and 72.43 (5-O—CH₂CH₂CH₂CH₂ CH₂—O—C₁₀H₇); 93.12 (C-8); 105.01(C-2″); 105.57 (C-4′); 105.93 (C-4a); 112.20 (C-3); 112.89 (C-6); 119.69(C-4″); 121.35 (C-8″); 124.91, 125.08, 126.17, 126.30 and 127.39 (C-3″,C-5″, C-6″, C-7″ and C-8a″); 133.97 (C-4a″); 139.30 (C-4); 145.82(C-5′); 148.73 (C-5); 152.07 (C-8a); 154.02 (C-1″); 157.60 (C-7); 160.02(C-2). IR (KBr): ν/cm⁻¹=2946, 2870, 1733, 1591, 1458, 1345. MS (EI): m/z(%)=414 M⁺ (82), 271 (28), 213 [C₁₅H₁₇O]⁺ (54), 144 (58), 115 (36), 69[C₅H₉]⁺ (100), 41 [C₃H₅]⁺ (85).

Example 46 5-[5-(2-Naphthyloxy)pentoxy]psoralen (AS134)4-[5-(2-Naphthyloxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on

Melting point: 118° C. Combustion analysis: C₂₆H₂₂O₅ (414.46)calculated: C 75.35 H 5.35 found: C 75.00 H 5.52

¹H-NMR (DMSO-d₆, 300 MHz): δ/ppm (TMS)=1.66-1.75 (m, 2H, 5-O—CH₂CH₂CH₂CH₂CH₂—O—C₁₀H₇); 1.84-1.96 (m, 1H, 5-O—CH₂CH ₂CH₂CH ₂CH₂—O—C₁₀H₇); 4.14(t, 2H, ³J=6.3 Hz, 5-O—CH₂CH₂CH₂CH₂CH ₂—O—C₁₀H₇); 4.53 (t, 2H, ³J=6.1Hz, 5-O—CH ₂CH₂CH₂CH₂CH₂—O—C₁₀H₇); 6.31 (d, 1H, ³J=9.8 Hz, H-3); 7.15(dd, 1H, ³J=8.9 Hz, ⁴J=2.4 Hz, H-3″); 7.31-7.36 (m, 4H, H-8, H-4′ und5-O—CH₂CH₂CH₂CH₂CH₂—O—C₁₀ H ₇); 7.45 (t, 1H, ³J=7.2 Hz, H-7″); 7.77-7-82(m, 3H, 5-O—CH₂CH₂CH₂CH₂CH₂—O—C₁₀H₇); 8.02 (d, 1H, ³J=2.3 Hz, H-5′);8.20 (d, 1H,³J=9.8 Hz, H-4). ¹³C-NMR (DMSO-d₆, 75 MHz): δ/ppm(TMS)=22.05 (5-O—CH₂CH₂ CH₂CH₂CH₂—O—C₁₀H₇); 28.26 and 29.02 (5-O—CH₂CH₂CH₂ CH₂CH₂—O—C₁₀H₇); 67.29 and 72.47 (5-O—CH₂CH₂CH₂ CH₂CH₂—O—C₁₀H₇);93.17 (C-8); 105.54 (C-4′); 106.02 (C-4a); 106.60 (C-1″); 112.28 (C-3);112.99 (C-6); 118.62 (C-3″); 123.39 (C-6″); 126.26, 126.55, 127.41,128.35 and 129.16 (C-4″, C-4a″, C-5″, C-7″ and C-8″); 134.25 (C-8a″);139.35 (C-4); 145.85 (C-5′); 148.72 (C-5); 152.07 (C-8a); 156.48 (C-2″);157.58 (C-7); 160.03 (C-2). IR (KBr): ν/cm⁻¹=3155, 3087, 2949, 2864,1716, 1626, 1546, 1342, 1259. MS (EI): m/z (%)=414 M⁺ (20), 271 (3), 213[C₁₅H₁₇O]⁺ (45), 202 [C₁₁H₆O₄]⁺ (13), 157 (45), 127 (31), 69 [C₅H₉]⁺(100), 41 [C₃H₅]⁺ (62)

Example 47 5-{4-(1-N-Pyrazolyl)butoxy}psoralen (PH 1)4-{4-(1-N-Pyrazolyl)butoxy}-7H-furo[3,2-g][1]benzopyran-7-on

500 mg (2.473 mmol) of 5-hydroxypsoralen and 893 mg (4.088 mmol) of4-iodo-1-chlorobutane were stirred at 25° C. in 30 ml of anhydrousacetone in the presence of an excess (2.0 g) of anhydrous potassiumcarbonate for 28 hours. The progress of the reaction was monitored bythin layer chromatography. After 28 hours the reaction mixture wasconcentrated under reduced pressure and distilled off the solvent almostcompletely. The oily residue was cooled and diluted with water. Theaqueous solution was then acidified with concentrated hydrochloric acidto pH 1. The slurry was stirred for 15-20 min and filtered. The solidswere washed with water to neutral pH and dried. The dried solids weresuspended in petroleum ether, filtered and dried under vacuum. To thesolids were added 400 mg (5.875 mmol) of pyrazole, 2.0 g anhydrouspotassium carbonate, catalytic amounts of potassium iodide, 30 ml of2-butanone and the reaction mixture was refluxed for 50 hours. After 50hours the reaction mixture was concentrated under vacuum. The residuewas diluted with water and acidified to pH 1 with concentratedhydrochloric acid. The separated oily organic layer was extracted with3×50 ml of dichloromethane. The dichloromethane layer was then washedwith 0.75% aqueous sodium hydroxide to separate the un-reacted5-hydroxypsoralen followed by washing with acidic water. Thedichloromethane layer was dried over anhydrous sodium sulfate andconcentrated. The residue was dissolved in an acetone-methanol mixture,treated with charcoal and re-crystallized from an ethylacetate-petroleum ether (20:80) mixture.

Yield: 108.6 mg (13.54%) Melting point: 145.6° C. ¹H-NMR (500 MHz,DMSO-d₆): δ [ppm]=8.17 (d, 1H, ³J=9.1 Hz, 3-H), 8.02 (s, 1H, 2′-H), 7.74(s, 1H, 5-OCH₂CH₂CH₂CH₂C₃ H ₃N₂), 7.43 (s, 1H, 5-OCH₂CH₂CH₂CH₂—C₃ H₃N₂), 7.34 (s, 1H, 8-H), 7.29 (s, 1H, 3′-H), 6.32 (d, 1H, ³J=9.1 Hz,4-H), 4.47 (s, 2H, 5-OCH ₂CH₂CH₂CH₂C₃H₃N₂), 4.20 (s, 2H, 5-OCH₂CH₂CH₂CH₂C₃H₃N₂), 2.0 (s, 2H, 5-OCH₂CH ₂CH ₂CH₂C₃H₃N₂), 1.75 (s, 2H, 5-OCH₂CH₂CH₂CH₂C₃H₃N₂). MS (70 eV) m/z: 324 (29%, M⁺), 202 (6%, [M-C₁₀H₁₂O]⁺), 174(6%, [202-CO]^(+),) 123 (99%), 81 (26%), 69 (13%). Combustion analysis:(FW: 324.34) % C, 65.83; % H, 4.96,% N, 7.36. (Calc. % C, 66.66; % H,4.97; % N, 8.64)

Example 48 5-{4-N-(4-Pvridinyl)aminobutoxy}psoralen (PH 3)4-{4-(4-N-Pyridinyl)aminobutoxy}-7H-furo[3,2-g][1]benzopyran-7-on

390 mg (1.334 mmol) of 5-(4-chlorobutoxy)psoralen and 628 mg (6.67 mmol)of 4-aminopyridine were refluxed in 20 ml of anhydrous acetonitrile inthe presence of catalytic amounts of potassium iodide for 45 hours. Theprogress of the reaction was monitored by thin layer chromatography.After 45 hours the reaction mixture was concentrated under reducedpressure. The oily residue was cooled, diluted with water and acidifiedwith 10% aqueous hydrochloric acid to pH 7-7.5. The slurry was stirredfor 15-20 min and filtered. The solids were dissolved in methanol,treated with charcoal and re-crystallized from 2% acidic acetone.

Yield: 171.5 mg (30.37%) Melting point: 133.9° C. ¹H-NMR (500 MHz,DMSO-d₆): δ [ppm]=8.272 (s, 1H, 5-OCH₂CH₂CH₂CH₂NHC₅H₄N), 8.25 (d, 2H,³J=7.41 Hz, 5-OCH₂CH₂CH₂CH₂NHC₅ H ₄N), 8.18 (d, 1H, ³J=9.8 Hz, 3-H),8.05 (d, 1H, ³J=2.6 Hz, 2′-H), 7.36 (s, 1H, 8-H), 7.33 (d, 1H, ³J=2.3Hz, 3′-H), 6.85 (d, 2H, ³J=7.32 Hz, 5-OCH₂CH₂CH₂CH₂NHC₅ H ₄N), 6.32 (d,1H, ³J=9.8 Hz, 4-H), 4.514 (t, 2H, ³J=6.06 Hz, 5-OCH ₂CH₂CH₂CH₂NHC₅H₄N),4.22 (t, 2H, ³J=6.98 Hz, 5-OCH₂CH₂CH₂CH ₂NHC₅H₄N), 1.99 (p, 2H, 5-OCH₂CH₂CH₂CH₂NHC₅H₄N), 1.77 (p, 2H, 5-OCH₂CH₂CH ₂CH₂NHC₅H₄N). MS (70 eV) m/z:350 (12%, M⁺), 202 (99%, [M-C₉H₁₂N₂]⁺), 174 (60%, [202-CO]⁺), 184 (20%),145 (11%), 123 (15%), 107 (46%), 94 (7%, C₅H₆N₂). Combustion analysis:(FW: 423.38) % C, 56.69; % H, 4.94; % N, 6.38. (Calc. % C, 56.68; % H,4.72; % N, 6.61)

Example 495-{4-(5″-Methyl-1″,3″,4″-thiadiazol-2″-thiolyl)butoxy}psoralen(PH 4)4-{4-(5″-Methyl-1″,3″,4″-thiadiazol-2″-thiolyl)butoxy}-7H-furo[3,2-g][1]benzopyran-7-on

500 mg (1.708 mmol) of 5-(4-chlorobutoxy)psoralen and 361 mg (2.733mmol) of 2-mercapto-1,3,4-thiadiazole were refluxed in 30 ml of2-butanone in the presence of an excess of anhydrous potassium carbonate(2.0 gm) and catalytic amounts of potassium iodide for 66 hours. Theprogress of the reaction was monitored by thin layer chromatography.After 66 hours the reaction mixture was concentrated under reducedpressure and distilled off the solvent almost completely. The oilyresidue was cooled, diluted with water and acidified with concentratedhydrochloric acid to pH 1. The slurry was stirred for 15-20 min andextracted with 100 ml of dichloromethane. The dichloromethane layer waswashed with 30 ml of 2% hydrochloric acid solution, dried over anhydroussodium sulfate and concentrated. The oily residue obtained was dissolvedin methanol, treated with charcoal and re-crystallized from a petroleumether-ethyl acetate (80:20) mixture.

Yield: 107 mg (16.13%) Melting point: 92.1° C. ¹H-NMR (500 MHz, CDCl₃):δ [ppm]=8.15 (d, 1H, ³J=9.79 Hz, 3-H), 7.59 (d, 1H, ³J=2.48 Hz, 2′-H),7.16 (s, 1H, 8-H), 6.95 (d, 1H, ³J=2.45 Hz, 3′-H), 6.29 (d, 1H, ³J=9.76Hz, 4-H), 4.51 (t, 2H, ³J=5.81 Hz, 5-OCH ₂CH₂CH₂CH₂S—), 3.43 (t, 2H,³J=6.88 Hz, 5-OCH₂CH₂CH₂CH ₂S—), 2.74 (s, 3H, 5″-CH₃), 2.09 (m, 4H,³J=3.00 Hz, 5-OCH₂CH ₂CH ₂CH₂S—). MS (70 eV) m/z : 388 (62%, M⁺), 202(14%, [M-C₇H₁₀N₂S₂]⁺), 187 (96%, C₇H₁₁N₂S₂), 174 (12%, [202-CO]⁺), 145(10%), 133 (32%), 99 (34%, C₃H₃N₂S), 87 (8%, C₄H₇S), 55 (28%, C₄H₇).Combustion analysis: (FW: 388.47) % C, 53.44; % H, 4.45; % N, 7.59; % S,16.77. (Calc. % C, 55.65; % H, 4.15; % N, 7.21; % S, 16.51)

Example 50 5-{4-(7-Coumarinyloxy)butoxy}psoralen (PH 5)4-{4-(7-Coumarinyloxy)butoxy}-7H-furo[3,2-g][1]benzopyran-7-on

500 mg (1.708 mmol) of 5-(4-chlorobutoxy)psoralen and 443 mg (2.733mmol) of 7-hydroxycoumarin were refluxed in 30 ml of 2-butanone in thepresence of an excess of anhydrous potassium carbonate (2.0 g) andcatalytic amounts of potassium iodide for 68 hours. The progress of thereaction was monitored by thin layer chromatography. After 68 hours thereaction mixture was concentrated under reduced pressure. The oilyresidue was cooled, diluted with water and acidified with concentratedhydrochloric acid to pH 1. The slurry was stirred for 15-20 min andextracted with 3×50 ml of dichloromethane. The dichloromethane layer wasextracted with 3×25 ml of 1% sodium hydroxide to separate the un-reacted7-hydroxycoumarin. The dichloromethane layer was washed with 30 ml of 2%hydrochloric acid, dried over anhydrous sodium sulfate and concentrated.The resulting oily residue was dissolved in methanol, treated withcharcoal and re-crystallized from a methanol-acetone (70:30) mixture.

Yield: 134.0 mg (18.75%) Melting point: 147° C. ¹H-NMR (500 MHz, CDCl₃):δ [ppm]=8.15 (d, 1H, ³J=9.80 Hz, 3-H), 7.64 (d, 1H, ³J=9.5 Hz,5-OCH₂CH₂CH₂CH₂OC₉ H ₅O₂), 7.61 (d, 1H, ³J=2.1 Hz, 2′-H), 7.36 (dd, 1H,³J=8.6 Hz, ⁵J=2.5 Hz, 5-OCH₂CH₂CH₂CH₂OC₉ H ₅O₂), 7.16 (s, 1H, 8-H), 6.99(d, 1H, ³J=2.1 Hz, 3′-H), 6.83 (m, 2H, 5-OCH₂CH₂CH₂CH₂OC₉ H ₅O₂), 6.26(d, 1H, ³J=9.50 Hz, 4-H), 6.20 (d, 1H, ³J=9.8 Hz, 5-OCH₂CH₂CH₂CH₂OC₉ H₅O₂), 4.57 (t, 2H, ³J=5.4 Hz, 5-OCH ₂CH₂CH₂CH₂OC₉H₅O₂), 4.15 (t, 2H,³J=5.0 Hz, 5-OCH₂CH₂CH₂CH ₂OC₉H₅O₂), 2.11 (m, 4H, ³J=2.6 Hz, 5-OCH₂CH₂CH ₂CH₂OC₉H₅O₂). MS (70 eV) m/z: 418 (34%, M⁺), 378 (68%), 217 (89%),202 (20%, [M-C₁₃H₁₂O₃]⁻), 175 (100%), 174 (14%, [202-CO]⁺), 187 (16%),145 (32%), 134 (26%), 89 (30%), 55 (48%, C₄H₇). Combustion analysis:(FW: 418.41) % C, 69.08; % H, 4.46. (Calc. % C, 68.90; % H, 4.34)

Example 51 5-{4-(5-Methoxy-1,3-benzothiazol-2-thiolyl)butoxy}psoralen(PH8)4-{4-(5-Methoxy-1,3-benzothiazol-2-thiolyl)butoxy}-7H-furo[3,2-g][1]benzopyran-7-on

539 mg (2.733 mmol) of 2-mercapto-5-methoxy-1,3-benzothiazole and 161 mg(2.869 mmol) of potassium hydroxide were refluxed in 25 ml of methanoluntil a clear solution was obtained. The solution was concentrated todryness under vacuum. To the solid potassium salt was added 20 ml ofanhydrous acetonitrile, 500 mg (1.708 mmol) of5-(4-chlorobutoxy)psoralen, 333 mg (2.221 mmol) of sodium iodide and theresulting mixture was refluxed for 69 hours. The progress of thereaction was monitored by thin layer chromatography. After 69 hours thereaction mixture was concentrated under reduced pressure. The oilyresidue was cooled, diluted with water and acidified with concentratedhydrochloric acid to pH 1. The slurry was stirred for 15-20 min andextracted with 100 ml of dichloromethane. The dichloromethane layer waswashed with 30 ml of 1% sodium hydroxide to separate the un-reacted2-mercaptobenzothiazole followed by 30 ml of 2% hydrochloric acid, driedover anhydrous sodium sulfate and concentrated. The resulting oilyresidue was dissolved in methanol, treated with charcoal andre-crystallized from a petroleum ether-acetone (80:20) mixture.

Yield: 599.8 mg (77.09%) Melting point: 134.8° C. ¹H-NMR (500 MHz,CDCl₃): δ [ppm]=8.09 (d, 1H, ³J=9.76 Hz, 3-H), 7.61 (d, 1H, ³J=8.9 Hzbenzothiazole), 7.58 (d, 1H, ³J=2.24 Hz, 2′-H), 7.35 (d, 1H, ⁴J=2.2 Hz,benzothiazole), 7.14(s, 1H, 8-H), 6.97 (dd, 1H, ³J=8.9 Hz, ⁴J=2.1 Hz,benzothiazole), 6.95 (d, 1H, ³J=2.76 Hz, 3′-H), 6.18 (d, 1H, ³J=9.78 Hz,4-H), 4.53 (t, 2H, ³J=5.78 Hz, 5-OCH ₂CH₂CH₂CH₂S—), 3.87 (s, 3H, O—CH₃), 3.48 (t, 2H, ³J=6.61 Hz, 5-OCH₂CH₂CH₂CH ₂S—), 2.11 (m, 4H, 5-OCH₂CH₂CH ₂CH₂S—). MS (70 eV) m/z: 455 (6%, M⁺), 453 (44%), 328 (28%), 252(100%, C₁₂H₁₄NOS₂), 201 (6%), 196 (12%, C₈H₆NOS₂), 174 (14%, [202-CO]⁺),145 (8%), 89 (6%), 55 (28%, C₄H₇). Combustion analysis: (FW: 455.56) %C, 60.70; % H, 4.49; % N, 3.09; % S, 13.94. (Calc. % C, 60.70; % H,4.65; % N, 3.07; % S, 14.08

Example 52 5-{4-(Pyrimidin-2-thiolyl)butoxy}psoralen(PH 9)4-{4-(Pyrimidin-2-thiolyl)butoxy}-7H-furo[3,2-g][1]benzopyran-7-on

306 mg (2.733 mmol) of 2-mercaptopyrimidine and 163 mg (2.87 mmol) ofpotassium hydroxide were refluxed in 50 ml methanol until a clearsolution was obtained. The solution was concentrated to dryness underreduced pressure. To the solid potassium salt was then added 30 ml ofanhydrous acetonitrile, 500 mg (1.708 mmol) of5-(4-chlorobutoxy)psoralen, 333 mg (2.220 mmol) of sodium iodide and theresulting mixture was refluxed for 67 hours. The progress of thereaction was monitored by thin layer chromatography. After 67 hours thereaction mixture was concentrated under reduced pressure and distilledoff the solvent almost completely. The oily residue was cooled anddiluted with water and then acidified with concentrated hydrochloricacid to pH 1. The slurry was stirred for 15-20 min and extracted with100 ml of dichloromethane. The dichloromethane layer was washed with 30ml of 1% sodium hydroxide to separate the un-reacted2-mercaptopyrimidine followed by 30 ml of 2% hydrochloric acid, driedover anhydrous sodium sulfate and concentrated. The oily residue wasdissolved in methanol, treated with charcoal and re-crystallized frommethanol.

Yield: 244 mg (38.78%) Melting point: 107-107.1° C. ¹H-NMR (500 MHz,CDCl₃): δ [ppm]=8.51 (d, 2H, pyrimidine), 8.14 (d, 1H, ³J=10.1 Hz, 3-H),7.59 (d, 1H, ³J=2.4 Hz, 2′-H), 7.16 (s, 1H, 8-H), 7.0 (t, 1H, ³J=4.89Hz, pyrimidine), 6.96 (d, 1H, ³J=1.5 Hz, 3′-H), 6.25 (d, 1H, ³J=9.8 Hz,4-H), 4.52 (t, 2H, ³J=5.8 Hz, 5-OCH ₂CH₂CH₂CH₂S—), 3.29 (t, 2H, ³J=6.8Hz, 5-OCH₂CH₂CH₂CH ₂S—), 2.01 (m, 4H, 5-OCH₂CH ₂CH ₂CH₂S—). MS (70 eV)m/z: 368 (27%, M⁺), 202 (8%, M-C₈H₁₀N₂S), 167 (100%, C₈H₁₁N₂S), 125(34%), 113 (37%), 55 (26%, C₄H₇). Combustion analysis: (FW: 368.41) % C,61.55; % H, 4.24; % N, 7.41; % S, 8.46 (Calc. % C, 61.94; % H, 4.38; %N, 7.60; % S, 8.70)

Example 53 5-(3-Cyanopropoxy)psoralen [ACP 1]4-(3-Cyanopropoxy)-7H-furo[3,2-g][1]benzopyran-7-on

800 mg (3.956 mmol) of 5-hydroxypsoralen and 0.7 ml (655.5 mg, 6.33mmol) of 4-chlorobutyronitrile were refluxed in 50 ml of 2-butanone inthe presence of an excess (2.6 g) of anhydrous potassium carbonate andcatalytic amounts of potassium iodide for 48 hours. The progress of thereaction was monitored by thin layer chromatography. After 48 hours thereaction mixture was concentrated under reduced pressure. The residualoily layer was cooled, diluted with water and acidified withconcentrated hydrochloric acid to pH 1. The slurry was stirred for 15-20min and then filtered. The solids were washed with water to neutral pH,dried bysuction and then further washed with petroleum ether. The driedsolids were dissolved in refluxing methanol, treated with charcoal andrecrystallized from methanol.

Yield: 710.2 mg (66.67%) Melting point: 155.2° C. ¹H-NMR (500 MHz,CDCl₃): δ [ppm]=8.13 (d, 1H, ³J=9.8 Hz, 3-H), 7.63 (d, 1H, ³J=2.0 Hz,2′-H), 7.21 (s, 1H, 8-H), 6.98 (d, 1H, ³J=2.0 Hz, 3′-H), 6.32 (d, 1H,³J=9.5 Hz, 4-H), 4.58 (t, 2H, ³J=5.8 Hz, 5-OCH ₂CH₂CH₂CN), 2.72 (t, 2H,³J=5.7 Hz, 5-OCH₂CH₂CH ₂CN), 2.26 (p, 2H, ³J=6.3 Hz, 5-OCH₂CH ₂CH₂CN).MS (70 eV) m/z : 269 (100%, M⁺), 202 (74%, [M-C₄H₅N]⁺), 174 (63%,[202-CO]⁺), 145 (26%), 118 (7%), 89 (14%). Combustion analysis: (FW:269.26) % C, 66.52; % H, 4.03; % N, 5.01. (Calc. % C, 66.91; % H, 4.12;% N, 5.01)

Example 54 5-(4-Phenyl-4-oxobutoxy)psoralen (KP 1)4-(4-Phenyl-4-oxobutoxy)-7H-furo[3,2-g][1]benzopyran-7-on

497 mg (2.720 mmol) of 4-chlorobutyrophenone and 445 mg (2.968 mmol) ofsodium iodide were refluxed in 30 ml acetone for 1.5 hours to obtain theiodo derivative. The reaction was monitored by TLC and also visually bythe precipitation of sodium chloride. To this slurry was added 500 mg(2.473 mmol) of 5-hydroxypsoralen, an excess (2 g) of anhydrouspotassium carbonate and it was refluxed for 140 hours. The progress ofthe reaction was monitored by thin layer chromatography. After 140 hoursthe reaction mixture was concentrated under reduced pressure. The oilyresidue was cooled and diluted with water. The aqueous solution was thenacidified with concentrated hydrochloric acid to pH 1. The slurry wasstirred for 15-20 min, filtered and washed with water and dried undervacuum. The solids were suspended in 50 ml ethyl acetate and refluxed toseparate the un-reacted 5-hydroxypsoralen. The ethyl acetate layer wasconcentrated, the resulting residue dissolved in 100 ml dichloromethaneand extracted with 25 ml of 1% sodium hydroxide to separate theremaining trace amounts of un-reacted 5-hydroxypsoralen. Thedichloromethane layer was washed with 30 ml of 2% hydrochloric acidsolution, dried over anhydrous sodium sulfate and concentrated. Thesolid residue obtained was dissolved in a methanol-acetone mixture,treated with charcoal and re-crystallized from a petroleum ether-acetone(90:10) mixture.

Yield: 295.2 mg (34.27%) Melting point: 129.1° C. ¹H-NMR (500 MHz,CDCl₃): δ [ppm]=8.13 (d, 1H, ³J=9.9 Hz, 3-H), 8.01 (d, 2H, ³J=7.9 Hz,⁴J=0.95 Hz, 2″-H, 6″-H), 7.62 (t, 1H, ³J=7.4 Hz, 3″-H, 5″-H), 7.60 (d,1H, ³J=2.4 Hz, 2′-H), 7.50 (t, 2H, ³J=7.7 Hz, 4″-H), 7.15 (s, 1H, 8-H),6.99 (d, 1H, ³J=2.5 Hz, 3′-H), 6.26 (d, 1H, ³J=9.8 Hz, 4-H) 4.59 (t, 2H,³J=6.2 Hz, 5-OCH ₂CH₂CH₂COC₆H₅), 3.28 (t, 2H, ³J=6.8 Hz, 5-OCH₂CH₂CH₂COC₆H₅), 2.38 (p, 2H, ³J=6.5 Hz, 5-OCH₂CH ₂CH₂COC₆H₅). MS (70 eV) m/z:348 (34%, M⁺), 202 (5%, M⁺-C₁₀H₁₀O), 147(99%, C₁₀H₁₀O), 174, (5%,[202-CO]⁺), 105 (71%, C₃H₆), 77 (33%, C₆H₅). Combustion analysis: (FW:348.36) % C, 71.68; % H, 5.25. (Calc. % C, 72.41; % H, 4.63)

Example 55 5-(4-Pentynyloxy)psoralen (AP1)4-(4-Pentynyloxy)-7H-furo[3,2-g][1]benzopyran-7-on

500 mg (2.473 mmol) of 5-hydroxypsoralen and 405.85 mg (3.957 mmol) of5-chloro-1-pentyne were refluxed in 30 ml of acetonitrile in thepresence of an excess of anhydrous potassium carbonate (2.0 gm) andcatalytic amounts of potassium iodide for 24 hours. The progress of thereaction was monitored by thin layer chromatography. After 24 hours thereaction mixture was concentrated under reduced pressure. The oilyresidue was cooled, diluted with water and acidified with concentratedhydrochloric acid to pH 1. The aqueous phase was extracted withdichloromethane. The dichloromethane phase was extracted with 25 ml of1% sodium hydroxide to separate the un-reacted 5-hydroxypsoralen. Thedichloromethane phase was washed with acidic water and then with waterto pH˜6-7. The organic phase was then dried over anhydrous sodiumsulphate and concentrated to dryness. The residue was dissolved inmethanol, decolorized with charcoal and re-crystallized from methanol.

Yield: 55 mg (8.29%) Melting point: 144.9-145.1° C. ¹H-NMR (500 MHz,CDCl₃): δ [ppm]=8.16 (d, 1H, ³J=9.77 Hz, 3-H), 7.60 (d, 1H, ³J=2.32 Hz,2′-H), 7.17 (s, 1H, 8-H), 7.01 (d, 1H, ³J=1.53 Hz, 3′-H), 6.29 (d, 1H,³J=9.78 Hz, 4-H), 4.56 (t, 2H, ³J=6.06 Hz, 5-OCH ₂CH₂CH₂CCH), 2.51 (q,2H, ³J=2.55 Hz, 5-OCH₂CH₂CH ₂CCH), 2.09 (p, 2H, ³J=6.44 Hz, 5-OCH₂CH₂CH₂CCH), 2.03 (t, 1H, ⁴J=2.59 Hz, 5-OCH₂CH₂CH₂CCH) MS (70 eV) m/z : 268(88%, M⁺), 203 (15%), 202 (100%, [M-C₅H₆]⁺), 175 (8%), 174 (11%,[202-CO]⁺), 173 (14%), 146 (7%), 145 (21%), 118(8%), 89 (10%), 67 (5%,C₅H₇) Combustion analysis: (FW: 268.27) % C, 71.25; % H, 4.38. (Calc. %C, 71.64; % H, 4.51)

Example 56 5-[4-(N-Phthalimido)butoxy]psoralen (PP1)4-[4-(N-Phthalimido)butoxy]-7H-furo[3,2-g][1]benzopyran-7-on

500 mg (2.473 mmol) of 5-hydroxypsoralen and 1.12 g (3.959 mmol) ofN-(4-bromobutyl)phthalimide were refluxed in 50 ml of acetonitrile inthe presence of an excess (2.2 g) of anhydrous potassium carbonate andcatalytic amounts of potassium iodide for 72 hours. The progress of thereaction was monitored by thin layer chromatography. After 72 hours thereaction mixture was concentrated under reduced pressure. The residuewas cooled and extracted with methanol. The slurry was filtered and thesolids were washed with methanol. The solids were then acidified with10% aqueous hydrochloric acid to pH˜1, filtered and washed with water toneutral pH and dried under vacuum. The solids were dissolved in acetone,treated with charcoal and recrystallized from methanol.

Yield: 260 mg (26.06%) Melting point: 177.9° C. ¹H-NMR (500 MHz, CDCl₃):δ [ppm]=8.14 (d, 1H, ³J=9.8 Hz, 3-H), 7.8 (dd, 4H, ³J=5.4 Hz, ⁴J=3.0 Hz,5-OCH₂CH₂CH₂CH₂NC₈ H ₄O₂), 7.6 (d, 1H, ³J=2.4 Hz, 2′-H), 7.13(s, 1H,8-H), 6.95 (d, 1H, ³J=1.6 Hz, 3′-H), 6.30 (d, 1H, ³J=9.8 Hz, 4-H), 4.5(t, 2H, ³J=5.7 Hz, 5-OCH ₂CH₂CH₂CH₂NC₈H₄O₂), 3.82 (t, 2H, ³J=6.6 Hz,5-OCH₂CH₂CH₂CH ₂NC₈H₄O₂), 1.98 (p, 4H, ³J=3.2 Hz, 5-OCH₂CH ₂CH₂CH₂NC₈H₄O₂). MS (70 eV) m/z: 403 (13%, M⁺), 202 (72%, [M-C₁₂H₁₁NO₂]⁺),202 (72%, C₁₂H₁₁NO₂), 174 (8%, [202-CO]⁺), 160 (99%), 148 (6%), 130(14%), 55 (5%, C₄H₇) Combustion analysis: (FW: 403.40) % C, 68.17%; % H,4.32; % N, 3.36 (Calc. % C, 68.48; % H, 4.25; % N, 3.47)

B. Data Comparing Inhibitory Activity On Different Potassium Channels

Appendix A sets forth examples of the inhibitory effects of certain5-phenoxyalkoxypsoralen compounds of the present invention on variouspotassium channels. These data indicate that certain of the compounds inthe present invention (especially those designated as PAP-1, AS78 andAS85 in Appendix A) are selective for Kv1.3 channels over Kv1.5channels. As explained above, inhibition of Kv1.5 potassium channels maycause clinically significant cardiac rhythm disturbances. Thus, theselectivity of these compounds for Kv1.3 channels over Kv1.5 channelsmay render these compounds useable for the treatment or prevention of abroad range of T cell mediated disorders and/or other disorders that maybe treated or prevented by inhibition of Kv1.3 channels, with little orno potential for cardiac arrhythmias due to untoward Kv1.5 channelinhibition.

C. Methods for Treating or Preventing Diseases or Disorders

The compositions of the present invention, as described above, and/orpharmaceutically acceptable salts or derivatives thereof, may beadministered to human or animal subjects in amount(s), on dosingschedule(s) and by route(s) of administration that are effective totreat or prevent diseases or disorders by inhibiting one or more typesof potassium channels. As shown in Appendix A, different compounds ofthe present invention exhibit different degrees of selectivity fordifferent types of potassium channels and, thus, specific compounds maybe selected on the basis of their potassium channel selectivity to treatspecific diseases or disorders. Although any suitable dosage may beused, the currently available information indicates that one or moredoses of about 0.1 mg/kg through about 10.0 mg/kg of a compound ofGeneral Formula I may be administered to humans to treat or prevent adisease or disorder, such as a T cell mediated disease or disorder. Theroute of administration may vary, depending on the particular compoundbeing given and/or the particular disease or disorder to be treated orprevented.

Example 57 Administration of5-(4-Phenoxybutoxy)7H-furo[3,2-g][1]benzopyran-7-on (PAP-1) for SystemicTreatment of T Cell Mediated Diseases

For example, 5-(4-Phenoxybutoxy)7H-furo[3,2-g][1]benzopyran-7-on (i.e.,the compound designated as PAP-1 in Example 1), or a pharmaceuticallyacceptable salt or derivative thereof, may be administered orally or byinjection (subcutaneous, intramuscular, intravenous, etc.) to humans inone or more daily doses of about 0.1 mg/kg through about 10.0 mg/kg tosystemically treat a T cell mediated autoimmune disorder. Such systemictreatment may be particularly suited for treatment of diseases anddisorders such as Type-1 diabetes, MS, graft vs. host disease ortransplant rejection, etc.

Example 58 Administration of5-(4-Phenoxybutoxy)7H-furo[3,2-g][1]benzopyran-7-on (PAP-1) for LocalTreatment of T Cell Mediated Diseases

For example, 5-(4-Phenoxybutoxy)7H-furo[3,2-g][1]benzopyran-7-on (i.e.,the compound designated as PAP-1 in Example 1), or a pharmaceuticallyacceptable salt or derivative thereof, may be administered topically orby local injection (e.g., intradermal, subcutaneous, intramuscular,etc.) to humans in one or more daily doses of about 0.1 mg/kg throughabout 10.0 mg/kg to locally treat a T cell mediated autoimmune disorder.Such local treatment may be particular suited for T cell mediateddiseases that cause cutaneous lesions, such as psoriasis, dermatitisherpetiformis, pemphigus vulgaris, mycosis fungoides, allergic contactdermatitis, atopic dermatitis, lichen planus and PLEVA (pityriasislichenoides et varioliforms acuta). In cases where the5-(4-Phenoxybutoxy)7H-furo[3,2-g][1]benzopyran-7-on is administeredtopically, it may be combined with a pharmaceutically acceptable carrierto from a topical preparation such as an ointment, cream, emulsion, gel,shampoo, liquid, patch, poltus, etc. The concentration of5-(4-Phenoxybutoxy)7H-furo[3,2-g][1]benzopyran-7-on within the topicalpreparation may be in the range of about 0.0001% by weight to about 1%by weight, although any suitable concentrations may be used.

It is to be appreciated that the invention has been described here abovewith reference to certain examples or embodiments of the invention butthat various additions, deletions, alterations and modifications may bemade to those examples and embodiments without departing from theintended spirit and scope of the invention. For example, any element orattribute of one embodiment or example may be incorporated into or usedwith another embodiment or example, unless to do so would render theembodiment or example unsuitable for its intended use. All reasonableadditions, deletions, modifications and alterations are to be consideredequivalents of the described examples and embodiments and are to beincluded within the scope of the following claims.

1. A composition of matter comprising a compound having the formula:

wherein: n is 1 through 10, cyclic or acyclic and optionally substitutedor unsubstituted; X is O, S, or N; and R1 is aryl, heterocyclyl orcycloalkyl and is optionally substituted with one or more substituentsselected from alkyl, alkoxy, amino and its alkyl derivatives, acylamino,carboxyl and its alkyl ester, cyano, halo, hydroxy, nitro andsulfonamido groups.
 2. A composition according to-claim 1 wherein thecompound comprises 4-(4-Phenoxybutoxy)-7H-furo[3,2-g][1]benzopyran-7-on.3. A composition according to claim 1 wherein the compound comprises4-(3-Phenoxypropoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 4. A compositionaccording to claim 1 wherein the compound comprises4-(2-Benzyloxyethoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 5. A compositionaccording to claim 1 wherein the compound comprises4-(4-Benzyloxybutoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 6. A compositionaccording to claim 1 wherein the compound comprises4-(3-Benzyloxypropoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 7. Acomposition of matter comprising4-(4-Chlorobutoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 8. A compositionaccording to claim 1 wherein the compound comprises4-(4-{2″-Methoxy-4″-nitrophenoxy}butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.9. A composition according to claim 1 wherein the compound comprises4-(4-{4″-Methyl-2″-nitrophenoxy}butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.10. A composition according to claim 1 wherein the compound comprises4-(4-{2″-Nitrophenoxy}butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 11. Acomposition according to claim 1 wherein the compound comprises4-(4-{3″-Nitrophenoxy}butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 12. Acomposition according to claim 1 wherein the compound comprises4-(4-{2″,4″-Dinitrophenoxy}butoxy)-7H-furo[3,2-g][1]benzopyran-7-on. 13.A composition according to claim 1 wherein the compound comprises4-(4-[4-Methoxyphenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 14. Acomposition according to claim 1 wherein the compound comprises4-(4-[3-Methoxyphenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 15. Acomposition according to claim 1 wherein the compound comprises4-(4-[3,5-Dimethoxyphenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on. 16.A composition according to claim 1 wherein the compound comprises4-(4-[4-Nitrophenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 17. Acomposition according to claim 1 wherein the compound comprises4-(4-[4-Chlorphenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 18. Acomposition according to claim 1 wherein the compound comprises4-(4-[4-Phenoxyphenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 19. Acomposition according to claim 1 wherein the compound comprises4-(4-[4-Methylphenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 20. Acomposition according to claim 1 wherein the compound comprises4-(4-[4-Ethylphenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 21. Acomposition according to claim 1 wherein the compound comprises4-(4-[4-Fluorphenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 22. Acomposition according to claim 1 wherein the compound comprises4-(4-[3-Trifluormethylphenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.23. A composition according to claim 1 wherein the compound comprises4-(4-[1-Naphthyloxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 24. Acomposition according to claim 1 wherein the compound comprises4-(4-[2-Naphthyloxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 25. Acomposition according to claim 1 wherein the compound comprises4-[3-(4-Methoxyphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 26. Acomposition according to claim 1 wherein the compound comprises4-[3-(3-Methoxyphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 27. Acomposition according to claim 1 wherein the compound comprises4-[3-(3,5-Dimethoxyphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.28. A composition according to claim 1 wherein the compound comprises4-[3-(4-Nitrophenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 29. Acomposition according to claim 1 wherein the compound comprises4-[3-(4-Chlorphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 30. Acomposition according to claim 1 wherein the compound comprises4-[3-(4-Phenoxyphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 31. Acomposition according to claim 1 wherein the compound comprises4-[3-(4-Methylphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 32. Acomposition according to claim 1 wherein the compound comprises4-[3-(4-Ethylphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 33. Acomposition according to claim 1 wherein the compound comprises4-[3-(4-Fluorphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 34. Acomposition according to claim 1 wherein the compound comprises4-[3-(3-Trifluormethylphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.35. A composition according to claim 1 wherein the compound comprises4-[3-(1-Naphthyloxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 36. Amethod according to claim 31 wherein the compound comprises4-[3-(2-Naphthyloxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 37. Acomposition according to claim 1 wherein the compound comprises4-(5-Phenoxypentoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 38. A compositionaccording to claim 1 wherein the compound comprises4-[5-(4-Methoxyphenoxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 39. Acomposition according to claim 1 wherein the compound comprises4-[5-(3,5-Dimethoxyphenoxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on.40. A composition according to claim 1 wherein the compound comprises4-[5-(4-Nitrophenoxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 41. Acomposition according to claim 1 wherein the compound comprises4-[5-(4-Chlorphenoxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 42. Acomposition according to claim 1 wherein the compound comprises4-[5-(4-Phenoxyphenoxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 43. Acomposition according to claim 1 wherein the compound comprises4-[5-(4-Methylphenoxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 44. Acomposition according to claim 1 wherein the compound comprises4-[5-(4-Ethylphenoxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 45. Acomposition according to claim 1 wherein the compound comprises4-[5-(4-Fluorphenoxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 46. Acomposition according to claim 1 wherein the compound comprises4-[5-(1-Naphthyloxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 47. Acomposition according to claim 1 wherein the compound comprises4-[5-(2-Naphthyloxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 48. Acomposition according to claim 1 wherein the compound comprises4-{4-(1-N-Pyrazolyl)butoxy}-7H-furo[3,2-g][1]benzopyran-7-on.
 49. Acomposition according to claim 1 wherein the compound comprises4-{4-(4-N-Pyridinyl)aminobutoxy}-7H-furo[3,2-g][1]benzopyran-7-on.
 50. Acomposition according to claim 1 wherein the compound comprises4-{4-(5″-Methyl-1″,3″,4″-thiadiazol-2″-thiolyl)butoxy}-7H-furo[3,2-g][1]benzopyran-7-on.51. A composition according to claim 1 wherein the compound comprises4-{4-(7-Coumarinyloxy)butoxy}-7H-furo[3,2-g][1]benzopyran-7-on.
 52. Acomposition according to claim 1 wherein the compound comprises4-{4-(5-Methoxy-1,3-benzothiazol-2-thiolyl)butoxy}-7H-furo[3,2-g][1]benzopyran-7-on.53. A composition according to claim 1 wherein the compound comprises4-{4-(Pyrimidin-2-thiolyl)butoxy}-7H-furo[3,2-g][1]benzopyran-7-on. 54.A composition of matter comprising4-(3-Cyanopropoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 55. A compositionof matter comprising4-(4-Phenyl-4-oxobutoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 56. Acomposition of matter comprising4-(4-Pentynyloxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 57. A composition ofmatter comprising4-[4-(N-Phthalimido)butoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 58. Amethod for treating or preventing, in a human or animal subject, a Tcell mediated autoimmune disease or disorder that can be treated byinhibition of potassium channels, said method comprising the step ofadministering to the subject, in an amount and form that is effective totreat the disease or disorder, a composition of matter comprising acompound having the formula:

wherein: n is 1 through 10, cyclic or acyclic and optionally substitutedor unsubstituted; X is O, or S, N; and R1 is aryl, heterocyclyl orcycloalkyl and is optionally substituted with one or more substituentsselected from alkyl, alkoxy, amino and its alkyl derivatives, acylamino,carboxyl and its alkyl ester, cyano, halo, hydroxy, nitro andsulfonamido groups; or a pharmaceutically acceptable salt or derivativeof said compound.
 59. A method according to claim 58 wherein the diseaseor disorder is a T cell mediated autoimmune disease or disorder.
 60. Amethod according to claim 59 wherein the compound inhibits Kv1.3channels.
 61. A method according to claim 60 wherein the compound has asubstantially greater affinity for inhibition of Kv1.3 than forinhibition of Kv1.5 channels.
 62. A method according to claim 60 whereinthe subject does not suffer from atrial fibrillation and wherein thecompound inhibits Kv1.3 channels sufficiently to treat or prevent thedisease or disorder but does not inhibit Kv1.5 channels sufficiently tocause cardiac arrhythmias.
 63. A method according to claim 61 whereinthe compound has an affinity for inhibition of Kv1.3 channels that is atleast 10 times greater than its affinity for inhibition of Kv1.5channels.
 64. A method according to claim 60 wherein the compound isadministered orally.
 65. A method according to claim 60 wherein thecompound is administered parenterally.
 66. A method according to claim60 wherein the compound is administered topically.
 67. A methodaccording to claim 58 wherein the compound comprises4-(4-Phenoxybutoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 68. A methodaccording to claim 58 wherein the compound comprises4-(3-Phenoxypropoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 69. A methodaccording to claim 58 wherein the compound comprises4-(2-Benzyloxyethoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 70. A methodaccording to claim 58 wherein the compound comprises4-(4-Benzyloxybutoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 71. A methodaccording to claim 58 wherein the compound comprises4-(3-Benzyloxypropoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 72. A methodfor treating, in a human or animal subject, a T cell mediated autoimmunedisease or disorder that can be treated by inhibition of potassiumchannels, said method comprising the step of administering to thesubject, in an amount and form that is effective to treat the disease ordisorder, a composition of matter comprising4-(4-Chlorobutoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 73. A methodaccording to claim 58 wherein the compound comprises4-(4-{2″-Methoxy-4″-nitrophenoxy}butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.74. A method according to claim 58 wherein the compound comprises4-(4-{4″-Methyl-2″-nitrophenoxy}butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.75. A method according to claim 58 wherein the compound comprises4-(4-{2″-Nitrophenoxy}butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 76. Amethod according to claim 58 wherein the compound comprises4-(4-{3″-Nitrophenoxy}butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 77. Amethod according to claim 58 wherein the compound comprises4-(4-{2″,4″-Dinitrophenoxy}butoxy)-7H-furo[3,2-g][1]benzopyran-7-on. 78.A method according to claim 58 wherein the compound comprises4-(4-[4-Methoxyphenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 79. Amethod according to claim 58 wherein the compound comprises4-(4-[3-Methoxyphenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 80. Amethod according to claim 58 wherein the compound comprises4-(4-[3,5-Dimethoxyphenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on. 81.A method according to claim 58 wherein the compound comprises4-(4-[4-Nitrophenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 82. Amethod according to claim 58 wherein the compound comprises4-(4-[4-Chlorphenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 83. Amethod according to claim 58 wherein the compound comprises4-(4-[4-Phenoxyphenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 84. Amethod according to claim 58 wherein the compound comprises4-(4-[4-Methylphenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 85. Amethod according to claim 58 wherein the compound comprises4-(4-[4-Ethylphenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 86. Amethod according to claim 58 wherein the compound comprises4-(4-[4-Fluorphenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 87. Amethod according to claim 58 wherein the compound comprises4-(4-[3-Trifluormethylphenoxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.88. A method according to claim 58 wherein the compound comprises4-(4-[1-Naphthyloxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 89. Amethod according to claim 58 wherein the compound comprises4-(4-[2-Naphthyloxy]butoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 90. Amethod according to claim 58 wherein the compound comprises4-[3-(4-Methoxyphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 91. Amethod according to claim 58 wherein the compound comprises4-[3-(3-Methoxyphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 92. Amethod according to claim 58 wherein the compound comprises4-[3-(3,5-Dimethoxyphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.93. A method according to claim 58 wherein the compound comprises4-[3-(4-Nitrophenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 94. Amethod according to claim 58 wherein the compound comprises4-[3-(4-Chlorphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 95. Amethod according to claim 58 wherein the compound comprises4-[3-(4-Phenoxyphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 96. Amethod according to claim 58 wherein the compound comprises4-[3-(4-Methylphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 97. Amethod according to claim 58 wherein the compound comprises4-[3-(4-Ethylphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 98. Amethod according to claim 58 wherein the compound comprises4-[3-(4-Fluorphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 99. Amethod according to claim 58 wherein the compound comprises4-[3-(3-Trifluormethylphenoxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.100. A method according to claim 58 wherein the compound comprises4-[3-(1-Naphthyloxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 101. Amethod according to claim 31 wherein the compound comprises4-[3-(2-Naphthyloxy)propoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 102. Amethod according to claim 58 wherein the compound comprises4-(5-Phenoxypentoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 103. A methodaccording to claim 58 wherein the compound comprises4-[5-(4-Methoxyphenoxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 104. Amethod according to claim 58 wherein the compound comprises4-[5-(3,5-Dimethoxyphenoxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on.105. A method according to claim 58 wherein the compound comprises4-[5-(4-Nitrophenoxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 106. Amethod according to claim 58 wherein the compound comprises4-[5-(4-Chlorphenoxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 107. Amethod according to claim 58 wherein the compound comprises4-[5-(4-Phenoxyphenoxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 108. Amethod according to claim 58 wherein the compound comprises4-[5-(4-Methylphenoxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 109. Amethod according to claim 58 wherein the compound comprises4-[5-(4-Ethylphenoxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 110. Amethod according to claim 58 wherein the compound comprises4-[5-(4-Fluorphenoxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 111. Amethod according to claim 58 wherein the compound comprises4-[5-(1-Naphthyloxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 112. Amethod according to claim 58 wherein the compound comprises4-[5-(2-Naphthyloxy)pentoxy]-7H-furo[3,2-g][1]benzopyran-7-on.
 113. Amethod according to claim 58 wherein the compound comprises4-{4-(1-N-Pyrazolyl)butoxy}-7H-furo[3,2-g][1]benzopyran-7-on.
 114. Amethod according to claim 58 wherein the compound comprises4-{4-(4-N-Pyridinyl)aminobutoxy}-7H-furo[3,2-g][1]benzopyran-7-on. 115.A method according to claim 58 wherein the compound comprises4-{4-(5″-Methyl-1″,3″,4″-thiadiazol-2″-thiolyl)butoxy}-7H-furo[3,2-g][1]benzopyran-7-on.116. A method according to claim 58 wherein the compound comprises4-{4-(7-Coumarinyloxy)butoxy}-7H-furo[3,2-g][1]benzopyran-7-on.
 117. Amethod according to claim 58 wherein the compound comprises4-{4-(5-Methoxy-1,3-benzothiazol-2-thiolyl)butoxy}-7H-furo[3,2-g][1]benzopyran-7-on.118. A method according to claim 58 wherein the compound comprises4-{4-(Pyrimidin-2-thiolyl)butoxy}-7H-furo[3,2-g][1]benzopyran-7-on. 119.A method for treating, in a human or animal subject, a T cell mediatedautoimmune disease or disorder that can be treated by inhibition ofpotassium channels, said method comprising the step of administering tothe subject, in an amount and form that is effective to treat thedisease or disorder, a composition of matter comprising4-(3-Cyanopropoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 120. A method fortreating, in a human or animal subject, a T cell mediated autoimmunedisease or disorder that can be treated by inhibition of potassiumchannels, said method comprising the step of administering to thesubject, in an amount and form that is effective to treat the disease ordisorder, a composition of matter comprising4-(4-oxobutoxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 121. A method fortreating, in a human or animal subject, a T cell mediated autoimmunedisease or disorder that can be treated by inhibition of potassiumchannels, said method comprising the step of administering to thesubject, in an amount and form that is effective to treat the disease ordisorder, a composition of matter comprising4-(4-Pentynyloxy)-7H-furo[3,2-g][1]benzopyran-7-on.
 122. A method fortreating, in a human or animal subject, a T cell mediated autoimmunedisease or disorder that can be treated by inhibition of potassiumchannels, said method comprising the step of administering to thesubject, in an amount and form that is effective to treat the disease ordisorder, a composition of matter comprising4-[4-(N-Phthalimido)butoxy]-7H-furo[3,2-g][1]benzopyran-7-on.